renal diseases
by subbia1988
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1. Acute renal failiure

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ACUTE RENAL FAILURE - Hugh R. Brady, Barry M. Brenner

INTRODUCTION

Acute renal failure (ARF) is a syndrome characterized by rapid decline in glomerular filtration rate (hours to days), retention of nitrogenous waste products, and perturbation of extracellular fluid volume and electrolyte and acid-base homeostasis. ARF complicates approximately 5% of hospital admissions and up to 30% of admissions to intensive care units. Oliguria (urine output 400 mL/d) is a frequent but not invariable clinical feature (~50%). ARF is usually asymptomatic and diagnosed when biochemical monitoring of hospitalized patients reveals a recent increase in blood urea and creatinine concentrations. It may complicate a wide range of diseases, which for purposes of diagnosis and management are conveniently divided into three categories: (1) diseases that cause renal hypoperfusion without compromising the integrity of renal parenchyma (prerenal ARF, prerenal azotemia) (~55%); (2) diseases that directly involve renal parenchyma (intrinsic renal ARF, renal azotemia) (~40%); and (3) diseases associated with urinary tract obstruction (postrenal ARF, postrenal azotemia) (~5%). Most ARF is reversible, the kidney being relatively unique among major organs in its ability to recover from almost complete loss of function. Nevertheless, ARF is associated with major in-hospital morbidity and mortality, in large part due to the serious nature of the illnesses that precipitate the ARF.

ETIOLOGY AND PATHOPHYSIOLOGY

PRERENAL ARF1 (PRERENAL AZOTEMIA)

Prerenal ARF1 is the most common form of ARF and represents a physiologic response to mild to moderate renal hypoperfusion. Prerenal ARF is by definition rapidly reversible upon restoration of renal blood flow and glomerular ultrafiltration pressure. Renal parenchymal tissue is not damaged; indeed, kidneys from individuals with prerenal ARF function well when transplanted into recipients with normal cardiovascular function. More severe hypoperfusion may lead to ischemic injury of renal parenchyma and intrinsic renal ARF (see below). Thus, prerenal ARF and intrinsic renal ARF due to ischemia are part of a spectrum of manifestations of renal hypoperfusion. As shown in Table 260-1, prerenal ARF can complicate any disease that induces hypovolemia, low cardiac output, systemic vasodilatation, or selective intrarenal vasoconstriction.

Hypovolemia leads to a fall in mean systemic arterial pressure, which is detected as reduced stretch by arterial (e.g., carotid sinus) and cardiac baroreceptors. Activated baroreceptors trigger a coordinated series of neural and humoral responses designed to restore blood volume and arterial pressure. These include activation of the sympathetic nervous system and renin-angiotensin-aldosterone system and release of arginine vasopressin (AVP; formerly called antidiuretic hormone). Norepinephrine, angiotensin II, and AVP act in concert in an attempt to preserve cardiac and cerebral perfusion by stimulating vasoconstriction in relatively "nonessential" vascular beds, such as the musculocutaneous and splanchnic circulations, by inhibiting salt loss through sweat glands, by stimulating thirst and salt appetite, and by promoting renal salt and water retention. Glomerular perfusion, ultrafiltration pressure, and filtration rate are preserved during mild hypoperfusion through several compensatory mechanisms. Stretch receptors in afferent arterioles, in response to a reduction in perfusion pressure, trigger afferent arteriolar vasodilatation through a local myogenic reflex (autoregulation). Biosynthesis of vasodilator prostaglandins (e.g., prostaglandin E2 and prostacyclin) is also enhanced, and these compounds preferentially dilate afferent arterioles. In addition, angiotensin II induces preferential constriction of efferent arterioles. As a result, intraglomerular pressure is maintained, the fraction of plasma flowing through glomerular capillaries that is filtered is increased (filtration fraction), and glomerular filtration rate (GFR) is preserved. During states of more severe hypoperfusion, these compensatory responses are overwhelmed and GFR falls, leading to prerenal ARF1.

Autoregulatory dilatation of afferent arterioles is maximal at mean systemic arterial blood pressures of ~80 mmHg, and hypotension below this level is associated with a precipitous decline in GFR2. Lesser degrees of hypotension may provoke prerenal ARF1 in the elderly and in patients with diseases affecting the integrity of afferent arterioles (e.g., hypertensive nephrosclerosis, diabetic vasculopathy). In addition, drugs that interfere with adaptive responses in the renal microcirculation may convert compensated renal hypoperfusion into overt prerenal ARF or trigger progression of prerenal ARF to ischemic intrinsic renal ARF (see below). Pharmacologic inhibitors of either renal prostaglandin biosynthesis [cyclooxygenase inhibitors; nonsteroidal anti-inflammatory drugs (NSAIDs)] or angiotensin-converting enzyme (ACE) activity (ACE inhibitors) and angiotensin II receptor blockers are the major culprits and should be used judiciously in the setting of suspected renal hypoperfusion. NSAIDs do not compromise GFR in healthy individuals but may precipitate prerenal ARF in patients with volume depletion or in those with chronic renal insufficiency in whom GFR is maintained, in part, through prostaglandin-mediated hyperfiltration by the remaining functional nephrons. ACE inhibitors should be used with special care in patients with bilateral renal artery stenosis or unilateral stenosis in a solitary functioning kidney. In these settings glomerular perfusion and filtration may be exquisitely dependent on the actions of angiotensin II. Angiotensin II preserves glomerular filtration pressure distal to stenoses by elevating systemic arterial pressure and by triggering selective constriction of efferent arterioles. ACE inhibitors blunt these responses and precipitate ARF, usually reversible, in ~30% of these patients.

Hepatorenal Syndrome This is a particularly aggressive form of ARF1, with many of the features of prerenal ARF, that frequently complicates hepatic failure due to advanced cirrhosis or other liver diseases, including malignancy, hepatic resection, and biliary obstruction. In full-blown hepatorenal syndrome, ARF progresses even after optimization of systemic hemodynamics and carries a mortality rate of 90%. The diagnosis and management of this condition are discussed in Chaps. 289 and 291.

INTRINSIC RENAL ARF1 (INTRINSIC RENAL AZOTEMIA)

Intrinsic renal ARF1 can complicate many diverse diseases of the renal parenchyma. From a clinicopathologic viewpoint, it is useful to divide the causes of intrinsic renal ARF into (1) diseases of larger renal vessels, (2) diseases of the renal microcirculation and glomeruli, (3) ischemic and nephrotoxic ARF, and (4) tubulointerstitial inflammation (Table 260-1). Most intrinsic renal ARF is triggered by ischemia (ischemic ARF) or nephrotoxins (nephrotoxic ARF), insults that classically induce acute tubular necrosis (ATN). Accordingly, the terms ARF and ATN are usually used interchangeably in these settings. However, as many as 20 to 30% of patients with ischemic or nephrotoxic ARF do not have clinical (granular or tubular cell urinary casts) or morphologic evidence of tubular necrosis, underscoring the role of sublethal injury to tubular epithelium and injury to other renal cells (e.g., endothelial cells) in the pathophysiology of this syndrome.

Etiology and Pathophysiology of Ischemic ARF1 Prerenal ARF and ischemic ARF are part of a spectrum of manifestations of renal hypoperfusion. Ischemic ARF differs from prerenal ARF in that the hypoperfusion induces ischemic injury to renal parenchymal cells, particularly tubular epithelium, and recovery typically takes 1 to 2 weeks after normalization of renal perfusion as it requires repair and regeneration of renal cells. In its most extreme form, ischemia leads to bilateral renal cortical necrosis and irreversible renal failure. Ischemic ARF occurs most frequently in patients undergoing major cardiovascular surgery or suffering severe trauma, hemorrhage, sepsis, and/or volume depletion (Table 260-1). Ischemic ARF can also complicate milder forms of true hypovolemia or reduced "effective" arterial blood volume if they occur in the presence of other insults (e.g., nephrotoxins or sepsis) or in patients with compromised autoregulatory defense mechanisms or preexisting renal disease.

The course of ischemic ARF1 is typically characterized by three phases: the initiation, maintenance, and recovery phases. The initiation phase (hours to days) is the initial period of renal hypoperfusion during which ischemic injury is evolving. GFR2 declines because (1) glomerular ultrafiltration pressure is reduced as a consequence of the fall in renal blood flow, (2) the flow of glomerular filtrate within tubules is obstructed by casts comprised of epithelial cells and necrotic debris derived from ischemic tubule epithelium, and (3) there is backleak of glomerular filtrate through injured tubular epithelium (Fig. 260-1). Ischemic injury is most prominent in the terminal medullary portion of the proximal tubule (S3 segment, pars recta) and the medullary portion of the thick ascending limb of the loop of Henle. Both segments have high rates of active (ATP-dependent) solute transport and oxygen consumption and are located in a zone of the kidney (the outer medulla) that is relatively ischemic, even under basal conditions, by virtue of the unique countercurrent arrangement of the medullary vasculature. Cellular ischemia results in a series of alterations in energetics, ion transport, and membrane integrity that ultimately lead to cell injury and, if severe, cell apoptosis or necrosis. These alterations include depletion of ATP, inhibition of active sodium transport and transport of other solutes, impairment of cell volume regulation and cell swelling, cytoskeletal disruption and loss of cell polarity, cell-cell and cell-matrix attachment, accumulation of intracellular calcium, altered phospholipid metabolism, oxygen free radical formation, and peroxidation of membrane lipids. Importantly, renal injury can be limited by restoration of renal blood flow during this period.

The initiation phase is followed by a maintenance phase (typically 1 to 2 weeks) during which renal cell injury is established, GFR2 stabilizes at its nadir (typically 5 to 10 mL/min), urine output is lowest, and uremic complications arise (see below). The reasons why the GFR remains low during this phase, despite correction of systemic hemodynamics, are still being defined. Putative mechanisms include persistent intrarenal vasoconstriction and medullary ischemia triggered by dysregulated release of vasoactive mediators from injured endothelial cells (e.g., decreased nitric oxide, increased endothelin-1, adenosine, and platelet-activating factor), congestion of medullary blood vessels, and reperfusion injury induced by reactive oxygen species and other mediators derived from leukocytes or renal parenchymal cells (Fig. 260-1). In addition, epithelial cell injury per se may contribute to persistent intrarenal vasoconstriction by a process termed tubuloglomerular feedback. Specialized epithelial cells in the macula densa region of distal tubules detect increases in distal salt (probably chloride) delivery that occur as a consequence of impaired reabsorption by more proximal nephron segments. Macula densa cells in turn stimulate constriction of adjacent afferent arterioles by a poorly defined mechanism and further compromise glomerular perfusion and filtration, thereby contributing to a vicious cycle. A recovery phase is characterized by renal parenchymal cell, particularly tubule epithelial cell, repair and regeneration and a gradual return of GFR to or towards premorbid levels. The recovery phase may be complicated by a marked diuretic phase due to excretion of retained salt and water and other solutes, continued use of diuretics, and/or delayed recovery of epithelial cell function (solute and water reabsorption) relative to glomerular filtration (see below).

Etiology and Pathophysiology of Nephrotoxic ARF1 Acute intrinsic renal ARF can complicate exposure to many structurally diverse pharmacologic agents (Table 260-1). With most nephrotoxins, the incidence of ARF is increased in the elderly and in patients with preexisting chronic renal insufficiency, true or "effective" hypovolemia, or concomitant exposure to other toxins.

Intrarenal vasoconstriction is a pivotal event in ARF1 that is triggered by radiocontrast agents (contrast nephropathy), cyclosporine, and tacrolimus (FK506). In keeping with this pathophysiology, both agents induce ARF that shares features with prerenal ARF: namely, an acute fall in renal blood flow and GFR2, a relatively benign urine sediment, and a low fractional excretion of sodium (see below). Severe cases may show clinical or pathologic evidence of ATN3. Contrast nephropathy classically presents as an acute (onset within 24 to 48 h) but reversible (peak 3 to 5 days, resolution within 1 week) rise in blood urea nitrogen and creatinine and is most common in individuals with preexisting chronic renal insufficiency, diabetes mellitus, congestive heart failure, hypovolemia, or multiple myeloma. The syndrome appears to be dose-related, and its incidence is only slightly reduced in high-risk individuals by use of more expensive low osmolality, nonionic contrast agents.

Direct toxicity to tubule epithelial cells and/or intratubular obstruction are major pathophysiologic events in ARF1 induced by many antibiotics and anticancer drugs. Frequent offenders are the antimicrobial agents, such as acyclovir, foscarnet, aminoglycosides, amphotericin B, and pentamidine, and chemotherapeutic agents, such as cisplatin, carboplatin, and ifosfamide. ARF complicates 10 to 30% of courses of aminoglycoside antibiotics, even in the presence of therapeutic levels. Amphotericin B causes dose-related ARF through intrarenal vasoconstriction and direct toxicity to proximal tubule epithelium. Cisplatin and carboplatin, like the aminoglycosides, are accumulated by proximal tubule cells and typically provoke ARF after 7 to 10 days of exposure by inducing mitochondrial injury, inhibition of ATPase activity and solute transport, free radical-mediated injury to cell membranes, apoptosis, and/or necrosis.

The most common endogenous nephrotoxins are calcium, myoglobin, hemoglobin, urate, oxalate, and myeloma light chains. Hypercalcemia can compromise GFR2, predominantly by inducing intrarenal vasoconstriction. Calcium phosphate deposition within the kidney may also contribute. Both rhabdomyolysis and hemolysis can induce ARF1, particularly in hypovolemic or acidotic individuals. Myoglobinuric ARF complicates approximately 30% of cases of rhabdomyolysis. Common causes of the latter include traumatic crush injury, acute muscle ischemia, seizures, excessive exercise, heat stroke or malignant hyperthermia, intoxications (e.g., alcohol, cocaine), and infectious or metabolic disorders. ARF due to hemolysis is relatively rare and is observed following massive blood transfusion reactions. It has been postulated that myoglobin and hemoglobin or other compounds released from muscle or red blood cells cause ARF via toxic effects on tubule epithelial cells, by promoting intrarenal oxidative stress and by inducing intratubular cast formation. Hypovolemia or acidosis may contribute to the pathogenesis of ARF in this setting by promoting intratubular cast formation. In addition, both hemoglobin and myoglobin are potent inhibitors of nitric oxide bioactivity and may trigger intrarenal vasoconstriction and ischemia in patients with borderline renal hypoperfusion. The formation of intratubular casts containing filtered immunoglobulin light chains and other proteins, including Tamm-Horsfall protein produced by thick ascending limb cells, is the major trigger for ARF in patients with multiple myeloma (myeloma cast nephropathy). In addition, light chains are directly toxic to tubule epithelial cells. Intratubular obstruction is also an important cause of ARF in patients with severe hyperuricosuria or hyperoxaluria. Acute uric acid nephropathy typically complicates treatment of lymphoproliferative or myeloproliferative disorders but occasionally occurs in other forms of primary or secondary hyperuricemia if the urine is concentrated.

Pathology of Ischemic and Nephrotoxic ARF1 The classic pathologic features of ischemic ARF1 are patchy and focal necrosis of tubule epithelium with detachment from its basement membrane and occlusion of tubule lumens with casts composed of intact or degenerating epithelial cells, cellular debris, Tamm-Horsfall mucoprotein, and pigments. Leukocyte accumulation is frequently observed in vasa recta; however, the morphology of the glomeruli and renal vasculature is characteristically normal. Necrosis is most severe in the straight portion (pars recta) of proximal tubules but may also affect the medullary thick ascending limb of the loop of Henle.

In nephrotoxic ARF1, morphologic changes tend to be most prominent in both the convoluted and straight portions of proximal tubules. Tubule cell necrosis is less pronounced than in ischemic ARF.

Other Causes of Intrinsic Renal ARF1 Patients with advanced atherosclerosis can develop ARF1 after manipulation of the aorta or renal arteries at surgery or angiography, following trauma, or, rarely, spontaneously due to embolization of cholesterol crystals to the renal vasculature (atheroembolic ARF). Cholesterol crystals lodge in small- and medium-sized arteries and incite a giant cell and fibrotic reaction in the vessel wall with narrowing or obstruction of the vessel lumen. Atheroembolic ARF is frequently irreversible. A myriad of structurally diverse pharmacologic agents induce ARF by triggering allergic interstitial nephritis, a disease characterized by infiltration of the tubulointerstitium by granulocytes (typically but not invariably eosinophils), macrophages, and/or lymphocytes and by interstitial edema. The most common offenders are antibiotics (e.g., penicillins, cephalosporins, trimethoprim, sulfonamides, rifampicin) and NSAIDs4 (Table 260-1).

POSTRENAL ARF1 (SEE ALSO CHAP. 270)

Urinary tract obstruction accounts for fewer than 5% of cases of ARF1. Because one kidney has sufficient clearance capacity to excrete the nitrogenous waste products generated daily, ARF from obstruction requires obstruction to urine flow between the external urethral meatus and bladder neck, bilateral ureteric obstruction, or unilateral ureteric obstruction in a patient with one functioning kidney or with preexisting chronic renal insufficiency. Bladder neck obstruction represents the most common cause of postrenal ARF and is usually due to prostatic disease (e.g., hypertrophy, neoplasia, or infection), neurogenic bladder, or therapy with anticholinergic drugs. Less common causes of acute lower urinary tract obstruction include blood clots, calculi, and urethritis with spasm. Ureteric obstruction may result from intraluminal obstruction (e.g., calculi, blood clots, sloughed renal papillae), infiltration of the ureteric wall (e.g., neoplasia), or external compression (e.g., retroperitoneal fibrosis, neoplasia or abscess, inadvertent surgical ligature). During the early stages of obstruction (hours to days), continued glomerular filtration leads to increased intraluminal pressure upstream to the site of obstruction. As a result there is gradual distention of the proximal ureter, renal pelvis, and calyces and a fall in GFR2. Acute obstruction is initially associated with modest increase in renal blood flow, but arteriolar vasoconstriction soon supervenes, leading to a further decline in glomerular filtration.

CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS

Patients presenting with renal failure should be assessed initially to determine if the decline in GFR2 is acute or chronic. An acute process is easily established if a review of laboratory records reveals a recent rise in blood urea and creatinine levels, but previous measurements are not always available. Findings that suggest chronic renal failure (Chap. 261) include anemia, neuropathy, and radiologic evidence of renal osteodystrophy or small scarred kidneys. However, it should be noted that anemia may also complicate ARF1 (see below), and renal size may be normal or increased in several chronic renal diseases (e.g., diabetic nephropathy, amyloidosis, polycystic kidney disease). Once a diagnosis of ARF has been established, several issues should be addressed promptly: (1) the identification of the cause of ARF, (2) the elimination of the triggering insult (e.g., nephrotoxin) and/or institution of disease-specific therapies, and (3) the prevention and management of uremic complications.

CLINICAL ASSESSMENT

Clinical clues to prerenal ARF1 are symptoms of thirst and orthostatic dizziness and physical evidence of orthostatic hypotension and tachycardia, reduced jugular venous pressure, decreased skin turgor, dry mucous membranes, and reduced axillary sweating. Case records should be reviewed for documentation of a progressive fall in urine output and body weight and recent initiation of treatment with NSAIDs4, ACE5 inhibitors, or angiotensin II receptor blockers. Careful clinical examination may reveal stigmata of chronic liver disease and portal hypertension, advanced cardiac failure, sepsis, or other causes of reduced "effective" arterial blood volume (Table 260-1).

Intrinsic renal ARF1 due to ischemia is likely following severe renal hypoperfusion complicating hypovolemic or septic shock or following major surgery. The likelihood of ischemic ARF is increased further if ARF persists despite normalization of systemic hemodynamics. Diagnosis of nephrotoxic ARF requires careful review of the clinical data and pharmacy, nursing, and radiology records for evidence of recent exposure to nephrotoxic medications or radiocontrast agents or to endogenous toxins (e.g., myoglobin, hemoglobin, uric acid, myeloma protein, or elevated levels of serum calcium).

Although ischemic and nephrotoxic ARF1 account for more than 90% of cases of intrinsic renal ARF, other renal parenchymal diseases must be considered (Table 260-2). Flank pain may be a prominent symptom following occlusion of a renal artery or vein and with other parenchymal diseases distending the renal capsule (e.g., severe glomerulonephritis or pyelonephritis). Subcutaneous nodules, livedo reticularis, bright orange retinal arteriolar plaques, and digital ischemia, despite palpable pedal pulses, are clues to atheroembolization. ARF in association with oliguria, edema, hypertension, and an "active" urine sediment (nephritic syndrome) suggests acute glomerulonephritis or vasculitis. Malignant hypertension is a likely cause of ARF in patients with severe hypertension and evidence of hypertensive injury to other organs (e.g., left ventricular hypertrophy and failure, hypertensive retinopathy and papilledema, neurologic dysfunction). Fever, arthralgias, and a pruritic erythematous rash following exposure to a new drug suggest allergic interstitial nephritis, although systemic features of hypersensitivity are frequently absent.

Postrenal ARF1 presents with suprapubic and flank pain due to distention of the bladder and of the renal collecting system and capsule, respectively. Colicky flank pain radiating to the groin suggests acute ureteric obstruction. Prostatic disease is likely if there is a history of nocturia, frequency, and hesitancy and enlargement or induration of the prostate on rectal examination. Neurogenic bladder should be suspected in patients receiving anticholinergic medications or with physical evidence of autonomic dysfunction. Definitive diagnosis of postrenal ARF hinges on judicious use of radiologic investigations and rapid improvement in renal function following relief of obstruction.

URINALYSIS

Anuria suggests complete urinary tract obstruction but may complicate severe cases of prerenal or intrinsic renal ARF1. Wide fluctuations in urine output raise the possibility of intermittent obstruction, whereas patients with partial urinary tract obstruction can present with polyuria due to impairment of urine concentrating mechanisms.

In prerenal ARF1, the sediment is characteristically acellular and contains transparent hyaline casts ("bland," "benign," "inactive" urine sediment). Hyaline casts are formed in concentrated urine from normal constitutents of urine — principally Tamm-Horsfall protein, which is secreted by epithelial cells of the loop of Henle. Postrenal ARF may also present with an inactive sediment, although hematuria and pyuria are common in patients with intraluminal obstruction or prostatic disease. Pigmented "muddy brown" granular casts and casts containing tubule epithelial cells are characteristic of ATN6 and suggest ischemic or nephrotoxic ARF. They are usually found in association with microscopic hematuria and mild "tubular" proteinuria (1 g/d); the latter reflects impaired reabsorption and processing of filtered proteins by injured proximal tubules. Casts are absent, however, in 20 to 30% of patients with ischemic or nephrotoxic ARF and are not a requisite for diagnosis. In general, red blood cell casts indicate glomerular injury or, less often, acute tubulointerstitial nephritis. White cell casts and nonpigmented granular casts suggest interstitial nephritis, whereas broad granular casts are characteristic of chronic renal disease and probably reflect interstitial fibrosis and dilatation of tubules. Eosinophiluria (5% of urine leukocytes) is a common finding (~90%) in antibiotic-induced allergic interstitial nephritis when studied using Hansel's stain; however, lymphocytes may predominate in allergic interstitial nephritis induced by NSAIDs4. Eosinophiluria is also a feature of atheroembolic ARF. Occasional uric acid crystals (pleomorphic in shape) are common in the concentrated urine of prerenal ARF but suggest acute urate nephropathy if seen in abundance. Oxalate (envelope-shaped) and hippurate (needle-shaped) crystals raise the possibility of ethylene glycol ingestion and toxicity.

Proteinuria of 1 g/d suggests injury to the glomerular ultrafiltration barrier ("glomerular proteinuria") or excretion of myeloma light chains. The latter are not detected by conventional dipsticks (which detect albumin) and must be sought by other means (e.g., sulfosalicylic acid test, immunoelectrophoresis). Heavy proteinuria is also a frequent finding (~80%) in patients who develop combined allergic interstitial nephritis and minimal change glomerulopathy when treated with NSAIDs4. A similar syndrome can be triggered by ampicillin, rifampicin, or interferon a. Hemoglobinuria or myoglobinuria should be suspected if urine is strongly positive for heme by dipstick, but contains few red cells, and if the supernatant of centrifuged urine is positive for free heme. Bilirubinuria may provide a clue to the presence of hepatorenal syndrome.

RENAL FAILURE INDICES

Analysis of urine and blood biochemistry is particularly useful for distinguishing prerenal ARF1 from ischemic or nephrotoxic intrinsic renal ARF (Table 260-3). The fractional excretion of sodium (FENa) is most useful in this regard. The FENa relates sodium clearance to creatinine clearance. Sodium is reabsorbed avidly from glomerular filtrate in patients with prerenal ARF, in an attempt to restore intravascular volume, but not in patients with ischemic or nephrotoxic intrinsic ARF, as a result of tubular epithelial cell injury. In contrast, creatinine is not reabsorbed in either setting. Consequently, patients with prerenal ARF typically have a FENa of 1.0% (frequently 0.1%), whereas the FENa in patients with ischemic or nephrotoxic ARF is usually 1.0%. The renal failure index (Table 260-3) provides comparable information, since clinical variations in serum sodium concentration are relatively small. Urine sodium concentration is a less sensitive index for distinguishing prerenal ARF from ischemic and nephrotoxic ARF as values overlap between groups. Similarly, indices of urinary concentrating ability such as urine specific gravity, urine osmolality, urine-to-plasma urea ratio, and blood urea-to-creatinine ratio are of limited value in differential diagnosis.

Many caveats apply when interpreting biochemical renal failure indices. FENa7 may be 1.0% in prerenal ARF1 if patients are receiving diuretics or have bicarbonaturia (accompanied by sodium to maintain electroneutrality), preexisting chronic renal failure complicated by salt wasting, or adrenal insufficiency. In contrast, the FENa is 1.0% in approximately 15% of patients with nonoliguric ischemic or nephrotoxic ARF, probably reflecting patchy injury to tubular epithelium with preservation of reabsorptive function in some areas. The FENa is also often 1.0% in ARF due to urinary tract obstruction, glomerulonephritis, and vascular diseases.

LABORATORY FINDINGS

Serial measurements of serum creatinine can provide useful pointers to the cause of ARF1. Prerenal ARF is typified by fluctuating levels that parallel changes in hemodynamic function. Creatinine rises rapidly (within 24 to 48 h) in patients with ARF following renal ischemia, atheroembolization, and radiocontrast exposure. Peak creatinine levels are observed after 3 to 5 days with contrast nephropathy and return to baseline after 5 to 7 days. In contrast, creatinine levels typically peak later (7 to 10 days) in ischemic ARF and atheroembolic disease. The initial rise in serum creatinine is characteristically delayed until the second week of therapy with many tubule epithelial cell toxins (e.g., aminoglycosides, cisplatin) and probably reflects the need for accumulation of these agents within cells before GFR2 falls.

Hyperkalemia, hyperphosphatemia, hypocalcemia, and elevations in serum uric acid and creatine kinase (MM isoenzyme) levels at presentation suggest a diagnosis of rhabdomyolysis. Hyperuricemia [890 umol/L (15 mg/dL)] in association with hyperkalemia, hyperphosphatemia, and increased circulating levels of intracellular enzymes such as lactate dehydrogenase may indicate acute urate nephropathy and tumor lysis syndrome following cancer chemotherapy. A wide serum anion and osmolal gap (measured serum osmolality minus the serum osmolality calculated from serum sodium, glucose, and urea concentrations) indicate the presence of an unusual anion or osmole in the circulation and are clues to diagnosis of ethylene glycol or methanol ingestion. Severe anemia in the absence of hemorrhage raises the possibility of hemolysis, multiple myeloma, or thrombotic microangiopathy. Systemic eosinophilia suggests allergic interstitial nephritis but is also a feature of atheroembolic disease and polyangiitis nodosa.

RADIOLOGIC FINDINGS

Imaging of the urinary tract by ultrasonography is useful to exclude postrenal ARF1. Computed tomography and magnetic resonance imaging are alternative imaging modalities. Whereas pelvicalyceal dilatation is usual with urinary tract obstruction (98% sensitivity), dilatation may be absent immediately following obstruction or in patients with ureteric encasement (e.g., retroperitoneal fibrosis, neoplasia). Retrograde or anterograde pyelography are more definitive investigations in complex cases and provide precise localization of the site of obstruction. A plain film of the abdomen, with tomography if necessary, is a valuable initial screening technique in patients with suspected nephrolithiasis. Doppler ultrasonography and magnetic resonance angiography are useful for assessment of patency of renal arteries and veins in patients with suspected vascular obstruction; however, contrast angiography is usually required for definitive diagnosis.

RENAL BIOPSY

Biopsy is reserved for patients in whom prerenal and postrenal ARF1 have been excluded and the cause of intrinsic renal ARF is unclear. Renal biopsy is particularly useful when clinical assessment and laboratory investigations suggest diagnoses other than ischemic or nephrotoxic injury that may respond to disease-specific therapy. Examples include glomerulonephritis, vasculitis, hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and allergic interstitial nephritis.

COMPLICATIONS

ARF1 impairs renal excretion of sodium, potassium, and water and perturbs divalent cation homeostasis and urinary acidification mechanisms. As a result, ARF is frequently complicated by intravascular volume overload, hyponatremia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypermagnesemia, and metabolic acidosis. In addition, patients are unable to excrete nitrogenous waste products and are prone to develop the uremic syndrome (Chap. 261). The speed of development and the severity of these complications reflect the degree of renal impairment and catabolic state of the patient.

Expansion of extracellular fluid volume is an inevitable consequence of diminished salt and water excretion in oliguric or anuric individuals. Whereas milder forms are characterized by weight gain, bibasilar lung rales, raised jugular venous pressure, and dependent edema, continued volume expansion may precipitate life-threatening pulmonary edema. Hypervolemia may be particularly problematic in patients receiving multiple intravenous medications and enteral or parenteral nutrition. Excessive administration of free water either through ingestion and nasogastric administration or as hypotonic saline or isotonic dextrose solutions (dextrose being metabolized) can induce hypoosmolality and hyponatremia, which, if severe, lead to cerebral edema and neurologic abnormalities, including seizures.

Hyperkalemia is a frequent complication of ARF1. Serum potassium typically rises by 0.5 mmol/L per day in oliguric and anuric patients due to impaired excretion of ingested or infused potassium and potassium released from injured tissue. Coexistent metabolic acidosis may exacerbate hyperkalemia by promoting potassium efflux from cells. Hyperkalemia may be particularly severe, even at the time of diagnosis, in patients with rhabdomyolysis, hemolysis, and tumor lysis syndrome. Mild hyperkalemia (6.0 mmol/L) is usually asymptomatic. Higher levels may trigger electrocardiographic abnormalities and/or arrythmias (Chap. 210).

Metabolism of dietary protein yields between 50 and 100 mmol/d of fixed nonvolatile acids that are normally excreted by the kidneys. Consequently, ARF1 is typically complicated by metabolic acidosis, often with an increased serum anion gap (Chap. 42). Acidosis can be particularly severe when endogenous production of hydrogen ions is increased by other mechanisms (e.g., diabetic or fasting ketoacidosis; lactic acidosis complicating generalized tissue hypoperfusion, liver disease, or sepsis; metabolism of ethylene glycol or methanol).

Mild hyperphosphatemia is an almost invariable complication of ARF1. Severe hyperphosphatemia may develop in highly catabolic patients or following rhabdomyolysis, hemolysis, or tumor lysis. Metastatic deposition of calcium phosphate can lead to hypocalcemia, particularly when the product of serum calcium (mg/dL) and phosphate (mg/dL) concentrations exceeds 70. Other factors that contribute to hypocalcemia include tissue resistance to the actions of parathyroid hormone and reduced levels of 1,25-dihydroxyvitamin D. Hypocalcemia is often asymptomatic but can cause perioral paresthesia, muscle cramps, seizures, hallucinations and confusion, and prolongation of the QT interval and nonspecific T-wave changes on electrocardiography (Chap. 332).

Anemia develops rapidly in ARF1 and is usually mild and multifactorial in origin. Contributing factors include impaired erythropoiesis, hemolysis, bleeding, hemodilution, and reduced red cell survival time. Prolongation of the bleeding time and leukocytosis are also common. Common contributors to the bleeding diathesis include mild thrombocytopenia, platelet dysfunction, and/or clotting factor abnormalities (e.g., factor VIII dysfunction), whereas leukocytosis usually reflects sepsis, a stress response, or other concurrent illness. Infection is a common and serious complication of ARF, occurring in 50 to 90% of cases and accounting for up to 75% of deaths. It is unclear whether patients with ARF have a clinically significant defect in host immune responses or whether the high incidence of infection reflects repeated breaches of mucocutaneous barriers (e.g., intravenous cannulae, mechanical ventilation, bladder catheterization). Cardiopulmonary complications of ARF include arrhythmias, myocardial infarction, pericarditis and pericardial effusion, pulmonary edema, and pulmonary embolism. Mild gastrointestinal bleeding is common (10 to 30%) and is usually due to stress ulceration of gastric or small intestinal mucosa.

Protracted periods of severe ARF1 are invariably associated with the development of the uremic syndrome (Chap. 261).

A vigorous diuresis can occur during the recovery phase of ARF1 (see above), which may on occasions be inappropriate and lead to intravascular volume depletion and delayed recovery of GFR2 by causing secondary prerenal ARF. Hypernatremia can also complicate recovery if water losses via hypotonic urine are not replaced or if losses are inappropriately replaced by relatively hypertonic saline solutions. Hypokalemia, hypomagnesemia, hypophosphatemia, and hypocalcemia are less common metabolic complications during this period.

TREATMENT

Prevention Because there are no specific therapies for ischemic or nephrotoxic ARF1, prevention is of paramount importance. Many cases of ischemic ARF can be avoided by close attention to cardiovascular function and intravascular volume in high-risk patients, such as the elderly and those with preexisting renal insufficiency. Indeed, aggressive restoration of intravascular volume has been shown to reduce dramatically the incidence of ischemic ARF after major surgery or trauma, burns, or cholera. The incidence of nephrotoxic ARF can be reduced by tailoring the dosage of nephrotoxic drugs to body size and GFR2; for example, reducing the dose or frequency of administration of drugs in patients with preexisting renal impairment. In this regard, it should be noted that serum creatinine is a relatively insensitive index of GFR and may overestimate GFR considerably in small or elderly patients. For purposes of drug dosing, it is advisable to estimate the GFR using the Cockcroft-Gault formula, which factors in the variables of age and weight (Chap. 40). Adjusting drug dosage according to circulating drug levels also appears to limit renal injury in patients receiving aminoglycoside antibiotics, cyclosporine, or tacrolimus. Diuretics, cyclooxygenase inhibitors, ACE8 inhibitors, angiotensin II receptor blockers, and other vasodilators should be used with caution in patients with suspected true or "effective" hypovolemia or renovascular disease as they may precipitate prerenal ARF or convert the latter to ischemic ARF. Allopurinol and forced alkaline diuresis are useful prophylactic measures in patients at high risk for acute urate nephropathy (e.g., cancer chemotherapy in hematologic malignancies) to limit uric acid generation and prevent precipitation of urate crystals in renal tubules. Forced alkaline diuresis may also prevent or attenuate ARF in patients receiving high-dose methotrexate or suffering from rhabdomyolysis. N-acetylcysteine limits acetaminophen-induced renal injury if given within 24 h of ingestion. Dimercaprol, a chelating agent, may prevent heavy metal nephrotoxicity. Ethanol inhibits ethylene glycol metabolism to oxalic acid and other toxic metabolites and is an important adjunct to hemodialysis in the emergency management of ethylene glycol intoxication.

Specific Therapies By definition, prerenal ARF1 is rapidly reversible upon correction of the primary hemodynamic abnormality, and postrenal ARF resolves upon relief of obstruction. To date, there are no specific therapies for established intrinsic renal ARF due to ischemia or nephrotoxicity. Management of these disorders should focus on elimination of the causative hemodynamic abnormality or toxin, avoidance of additional insults, and prevention and treatment of complications. Specific treatment of other causes of intrinsic renal ARF depends on the underlying pathology.

PRERENAL ARF1 The composition of replacement fluids for treatment of prerenal ARF1 due to hypovolemia must be tailored according to the composition of the lost fluid. Severe hypovolemia due to hemorrhage should be corrected with packed red cells, whereas isotonic saline is usually appropriate replacement for mild to moderate hemorrhage or plasma loss (e.g., burns, pancreatitis). Urinary and gastrointestinal fluids can vary greatly in composition but are usually hypotonic. Hypotonic solutions (e.g., 0.45% saline) are usually recommended as initial replacement in patients with prerenal ARF due to increased urinary or gastrointestinal fluid losses, although isotonic saline may be more appropriate in severe cases. Subsequent therapy should be based on measurements of the volume and ionic content of excreted or drained fluids. Serum potassium and acid-base status should be monitored carefully, and potassium and bicarbonate supplemented as appropriate. Cardiac failure may require aggressive management with positive inotropes, preload and afterload reducing agents, antiarrhythmic drugs, and mechanical aids such as intraaortic balloon pumps. Invasive hemodynamic monitoring may be required to guide therapy for complications in patients in whom clinical assessment of cardiovascular function and intravascular volume is difficult.

Fluid management may be particularly challenging in patients with cirrhosis complicated by ascites. In this setting, it is important to distinguish between full-blown hepatorenal syndrome (Chap. 289), which carries a grave prognosis, and reversible ARF1 due to true or "effective" hypovolemia induced by overzealous use of diuretics or sepsis (e.g., spontaneous bacterial peritonitis). The contribution of hypovolemia to ARF can be definitively assessed only by administration of a fluid challenge. Fluids should be administered slowly and titrated against jugular venous pressure and, if necessary, central venous and pulmonary capillary wedge pressure, abdominal girth, and urine output. Patients with a reversible prerenal component typically have an increase in urine output and fall in serum creatinine, whereas patients with hepatorenal syndrome do not and may suffer increased ascites formation and pulmonary compromise if not monitored closely. Large volumes of ascitic fluid can usually be drained by paracentesis without deterioration in renal function if intravenous albumin is administered simultaneously. Indeed, "large-volume paracentesis" may afford an increase in GFR2, possibly by lowering intraabdominal pressure and improving flow in renal veins. Shunting of ascitic fluid from the peritoneum to a central vein (peritoneojugular shunt, LeVeen or Denver shunts) is an alternative approach in refractory cases but has not been shown to improve survival in controlled trials. The efficacy of the newer technique of transjugular intrahepatic portosystemic shunting (TIPS procedure) is currently undergoing rigorous clinical assessment. Shunting can also improve GFR and sodium excretion transiently, probably because the increase in central blood volume stimulates release of atrial natriuretic peptides (ANPs) and inhibits secretion of aldosterone and norepinephrine.

INTRINSIC RENAL ARF1 Many different approaches have been tested for their ability to attenuate injury or hasten recovery in ischemic and nephrotoxic ARF1. These include ANP9, low-dose dopamine, endothelin antagonists, loop-blocking diuretics, calcium channel blockers, a-adrenoreceptor blockers, prostaglandin analogues, antioxidants, antibodies against leukocyte adhesion molecules, and insulin-like growth factor type I. Whereas many of these are beneficial in experimental models of ischemic or nephrotoxic ARF, they have either failed to confer consistent benefit or proved ineffective in humans.

ARF1 due to other intrinsic renal diseases such as acute glomerulonephritis or vasculitis may respond to glucocorticoids, alkylating agents, and/or plasmapheresis, depending on the primary pathology. Glucocorticoids also hasten remission in some cases of allergic interstitial nephritis. Aggressive control of systemic arterial pressure is of paramount importance in limiting renal injury in malignant hypertensive nephrosclerosis, toxemia of pregnancy, and other vascular diseases. Hypertension and ARF due to scleroderma may be exquisitely sensitive to treatment with ACE10 inhibitors.

POSTRENAL ARF1 Management of postrenal ARF requires close collaboration between nephrologist, urologist, and radiologist. Obstruction of the urethra or bladder neck is usually managed initially by transurethral or suprapubic placement of a bladder catheter, which provides temporary relief while the obstructing lesion is identified and treated definitively. Similarly, ureteric obstruction may be treated initially by percutaneous catheterization of the dilated renal pelvis or ureter. Indeed, obstructing lesions can often be removed percutaneously (e.g., calculus, sloughed papilla) or bypassed by insertion of a ureteric stent (e.g., carcinoma). Most patients experience an appropriate diuresis for several days following relief of obstruction. Approximately 5% of patients develop a transient salt-wasting syndrome that may require administration of intravenous saline to maintain blood pressure.

Supportive Measures (Table 260-4) Following correction of hypovolemia, salt and water intake are tailored to match losses. Hypervolemia can usually be managed by restriction of salt and water intake and diuretics. Indeed, there is, as yet, no proven rationale for administration of diuretics in ARF1 except to treat this complication. High doses of loop-blocking diuretics such as furosemide (up to 200 to 400 mg intravenously) or bumetanide (up to 10 mg intravenously administered as a bolus or by continuous infusion) may promote diuresis in patients who fail to respond to conventional doses. Despite the fact that subpressor doses of dopamine may transiently promote salt and water excretion by increasing renal blood flow and GFR2 and by inhibiting tubule sodium reabsorption, subpressor ("low-dose," "renal-dose,") dopamine has proved ineffective in clinical trials, may trigger arrythmias and sudden cardiac death in critically ill patients, and should not be used as a renoprotective agent in this setting. Ultrafiltration or dialysis is used to treat severe hypervolemia when conservative measures fail. Hyponatremia and hypoosmolality can usually be controlled by restriction of free water intake. Conversely, hypernatremia is treated by administration of water or intravenous hypotonic saline or isotonic dextrose-containing solutions. The management of hyperkalemia is described in Chap. 41.

Metabolic acidosis is not usually treated unless serum bicarbonate concentration falls below 15 mmol/L or arterial pH falls below 7.2. More severe acidosis is corrected by oral or intravenous sodium bicarbonate. Initial rates of replacement are guided by estimates of bicarbonate deficit and adjusted thereafter according to serum levels (Chap. 42). Patients are monitored for complications of sodium bicarbonate administration such as hypervolemia, metabolic alkalosis, hypocalcemia, and hypokalemia. From a practical point of view, most patients requiring sodium bicarbonate need emergency dialysis within days. Hyperphosphatemia is usually controlled by restriction of dietary phosphate and by oral aluminum hydroxide or calcium carbonate, which reduce gastrointestinal absorption of phosphate. Hypocalcemia does not usually require treatment unless severe, as may occur with rhabdomyolysis or pancreatitis or following admininstration of bicarbonate. Hyperuricemia is typically mild [890 umol/L ( 15 mg/dL)] and does not require intervention.

The objective of nutritional management during the maintenance phase of ARF1 is to provide sufficient calories to avoid catabolism and starvation ketoacidosis, while minimizing production of nitrogenous waste. This is best achieved by restricting dietary protein to approximately 0.6 g/kg per day of protein of high biologic value (i.e., rich in essential amino acids) and to provide most calories as carbohydrate (approximately 100 g daily). Nutritional management is easier in nonoliguric patients and following institution of dialysis. Vigorous parenteral hyperalimentation is claimed to improve prognosis; however, convincing benefit has yet to be demonstrated in controlled trials.

Anemia may necessitate blood transfusion if severe or if recovery is delayed. In contrast to chronic renal failure, recombinant human erythropoietin is rarely used in ARF1 because bone marrow resistance to erythropoietin is common, more immediate treatment of anemia (if any) is required, and renal failure is usually self-limiting. Uremic bleeding usually responds to correction of anemia, administration of desmopressin or estrogens, or dialysis. Regular doses of antacids appear to reduce the incidence of gastrointestinal hemorrhage significantly and may be more effective in this regard than H2 antagonists or proton pump inhibitors. Meticulous care of intravenous cannulae, bladder catheters, and other invasive devices is mandatory to avoid infections. Unfortunately, prophylactic antibiotics have not been shown to reduce the incidence of infection in these high-risk patients.

INDICATIONS AND MODALITIES OF DIALYSIS (SEE ALSO CHAP. 262) Dialysis replaces renal function until regeneration and repair restore renal function. Hemodialysis and peritoneal dialysis appear equally effective for management of ARF1. Thus, the dialysis modality is chosen according to the needs of individual patients (e.g., peritoneal dialysis may be preferable if the patient is hemodynamically unstable, and hemodialysis after abdominal surgery involving the peritoneum), the expertise of the nephrologist, and the facilities of the institution. Vascular access for conventional intermittent hemodialysis is best achieved by insertion of a temporary double-lumen hemodialysis catheter into the internal jugular vein. The subclavian and femoral veins are alternative access sites. Peritoneal dialysis is achieved by insertion of a cuffed catheter into the peritoneal cavity. Absolute indications for dialysis include symptoms or signs of the uremic syndrome and management of refractory hypervolemia, hyperkalemia, or acidosis. Most nephrologists also initiate dialysis empirically for blood urea levels of 100 mg/dL, even in the absence of clinical uremia; however, this approach has yet to be validated in controlled clinical trials. Recent evidence suggests that more intensive hemodialysis (e.g., daily rather than alternate-day intermittent dialysis) is clinically superior and confers improved survival in ARF once dialysis is required. This conclusion may not be as intuitive as it first appears as dialysis itself has been postulated to prolong the period of oliguria in some cases by inducing hypotension and further renal ischemia and through activation of leukocytes on the dialysis membrane, which may then proceed to aggravate renal injury.

Continuous renal replacement therapies (CRRTs) are alternatives to conventional intermittent hemodialysis techniques for treatment of ARF1. They are particularly valuable techniques in patients in whom intermittent hemodialysis fails to control hypervolemia or uremia and for those who do not tolerate intermittent hemodialysis and in whom peritoneal dialysis is not possible. Continuous arteriovenous hemodiafiltration (CAVHD) requires both arterial and venous access. The patient's own blood pressure generates an ultrafiltrate of plasma across a porous biocompatible dialysis membrane. A physiologic crystalloid solution is passed along the other side of the membrane to achieve diffusive clearance. Continuous venovenous hemodiafiltration (CVVHD), in contrast, requires only a double-lumen venous catheter as a blood pump generates ultrafiltration pressure across the dialysis membrane. In the more simple techniques of continuous arteriovenous hemofiltration (CAVH) and continuous venovenous hemofiltration (CVVH) the dialysis step is eliminated and an ultrafiltrate of plasma is removed across the dialysis membrane and replaced by a physiologic crystalloid solution. The bulk of evidence to date suggests that intermittent and continuous dialytic therapies are equally effective in the context of ARF. The choice of technique is currently tailored to the specific needs of the patient, the resources of the institution, and the expertise of the physician. Potential disadvantages of continuous hemodialysis techniques are the need for prolonged immobilization in bed, systemic anticoagulation, arterial cannulation (in CAVH11), and prolonged exposure of blood to synthetic, albeit relatively biocompatible, dialysis membranes.

OUTCOME AND LONG-TERM PROGNOSIS

The mortality rate among patients with ARF1 approximates 50% and has changed little over the past 30 years. It should be stressed, however, that patients usually die from sequelae of the primary illness that induced ARF and not from ARF itself. Indeed, the kidney is one of the few organs whose function can be replaced artificially (i.e., by dialysis) for protracted periods of time. In agreement with this interpretation, mortality rates vary greatly depending on the cause of ARF: ~15% in obstetric patients, ~30% in toxin-related ARF, and ~60% following trauma or major surgery. Oliguria (400 mL/d) at time of presentation and a rise in serum creatinine of 265 umol/L (3 mg/dL) are associated with a poor prognosis and probably reflect the severity of renal injury and of the primary illness. Mortality rates are higher in older debilitated patients and in those with multiple organ failure. Most patients who survive an episode of ARF recover sufficient renal function to live normal lives. However, 50% have subclinical impairment of renal function or residual scarring on renal biopsy. Approximately 5% of patients never recover function and require long-term renal replacement with dialysis or transplantation. An additional 5% suffer progressive decline in GFR2, following an initial recovery phase, probably due to hemodynamic stress and sclerosis of remnant glomeruli.


	2. Chronic renal failiure

Disclaimer: Not mine.. no money made.. don't sue me..

CHRONIC RENAL FAILURE - Karl Skorecki, Jacob Green*, Barry M. Brenner

NOTE

*Deceased

MECHANISMS OF CHRONIC RENAL FAILURE

DEFINITIONS

Chronic renal disease (CRD) is a pathophysiologic process with multiple etiologies, resulting in the inexorable attrition of nephron number and function and frequently leading to end-stage renal disease (ESRD). In turn, ESRD represents a clinical state or condition in which there has been an irreversible loss of endogenous renal function, of a degree sufficient to render the patient permanently dependent upon renal replacement therapy (dialysis or transplantation) in order to avoid life-threatening uremia. Uremia is the clinical and laboratory syndrome, reflecting dysfunction of all organ systems as a result of untreated or undertreated acute or chronic renal failure. Given the capacity of the kidneys to regain function following acute injury (Chap. 260), the vast majority (90%) of patients with ESRD have reached this state as a result of CRD.

PATHOPHYSIOLOGY OF CRD (SEE ALSO CHAP. 259)

The pathophysiology of CRD1 involves initiating mechanisms specific to the underlying etiology as well as a set of progressive mechanisms that are a common consequence following long-term reduction of renal mass, irrespective of etiology. Such reduction of renal mass causes structural and functional hypertrophy of surviving nephrons. This compensatory hypertrophy is mediated by vasoactive molecules, cytokines, and growth factors and is due initially to adaptive hyperfiltration, in turn mediated by increases in glomerular capillary pressure and flow. Eventually, these short-term adaptations prove maladaptive, in that they predispose to sclerosis of the remaining viable nephron population. Increased intrarenal activity of the renin-angiotensin axis appears to contribute both to the initial adaptive hyperfiltration and to the subsequent maladaptive hypertrophy and sclerosis.

The definition of CRD1 requires that the pathophysiologic process described above last more than 3 months. A recently widely accepted international classification divides CRD into a number of stages (Table 261-1) defined by clinical estimation of the glomerular filtration rate (GFR). These stages help guide clinical diagnostic and management approaches. First, it is important to identify factors that increase the risk for CRD, even in individuals with normal GFR. Such factors include family history of heritable renal disease, hypertension, diabetes, autoimmune disease, older age, past episode of acute renal failure, and current evidence of kidney damage with normal or even increased GFR. Such evidence of kidney damage in the face of normal or increased GFR places affected individuals into stage 1 CRD and includes proteinuria, abnormal urinary sediment, or urinary tract structural abnormalities (e.g., vesicoureteric reflux) evident on imaging studies. Even at this stage, when baseline GFR is normal, there is often a characteristic loss of renal reserve. This early stage is particularly well documented in diabetic nephropathy. Further stages in the pathogenesis of CRD are characterized by a progressive decline in estimated GFR with mild, moderate, and severe stages defined at GFR levels (mL/min per 1.73 m2) of 60 to 89, 30 to 59, and 15 to 29, respectively. At a GFR 15 mL/min per 1.73 m2, renal replacement therapy may be indicated if uremia is present. For purposes of staging CRD, current guidelines recommend estimating GFR using one of the two equations shown in Table 261-2, based on measured plasma creatinine concentration, age, gender, and ethnic origin. The normal annual mean decline in GFR with age beginning at age 20 to 30 years is 1 mL/min per 1.73 m2, reaching a mean value in males of 70 at age 70. GFR is slightly lower in women than men. By the time plasma creatinine concentration is even mildly elevated, substantial chronic nephron injury has already occurred.

Albuminuria serves as a key adjunctive tool for monitoring nephron injury and response to therapy in many forms of CRD1. Current guidelines recommend use of albumin-specific dipstick measurement or quantitation by measurement of albumin-to-creatinine ratio in a spot first morning urine sample. Persistence of 17 mg albumin per gram of creatinine in adult males and 25 mg albumin per gram of creatinine in adult females usually signifies chronic renal damage, irrespective of GFR2, and can be followed in monitoring natural history and response to therapy, especially in CRD consequent to diabetes, hypertension, or glomerulonephritis. Further considerations in the overall clinical approach to proteinuria are provided in Chap. 40.

During stages 1 and 2 CRD1, patients often remain free of symptoms, other than those that might accompany the underlying etiologic process causing renal disease. As the decline in GFR2 progresses to stages 3 and 4 (GFR 60 mL/min per 1.73 m2), clinical and laboratory complications of CRD become progressively more prominent. Virtually all organ systems are affected, but the most evident complications include anemia and loss of energy; decreasing appetite and disturbances in nutritional status; abnormalities in calcium and phosphorus metabolism accompanied by metabolic bone disease; and abnormalities in sodium, water, potassium, and acid-base homeostasis. When GFR falls to 15 mL/min per 1.73 m2, patients usually experience a severe disturbance in their activities of daily living, sense of well-being, nutritional status, and water and electrolyte homeostasis, eventuating in an overtly uremic state wherein continued survival without renal replacement therapy becomes impossible.

ETIOLOGY AND EPIDEMIOLOGY

It has been estimated that at least 6% of the adult U.S. population have chronic renal damage with a GFR2 60 mL/min per 1.73 m2 (stages 1 and 2 CRD1) and hence are at imminent risk of a progressive further decline in GFR. An additional ~4.5% of the U.S. population are in stages 3 and 4 CRD. Diabetic and hypertensive nephropathy are the leading underlying etiologies of both CRD and ESRD3. Hypertension is a particularly common cause and consequence of CRD in the elderly, in whom chronic renal ischemia due to renovascular disease may be an underrecognized additional contribution to the pathophysiologic process. It should be noted that cardiovascular mortality precludes most patients with CRD from reaching the stage of ESRD. Identification of CRD as a major risk factor for cardiovascular morbidity and mortality, and the expectation of effective interventions to diminish premature cardiovascular mortality, and increasing longevity overall, will increase the cohort of patients reaching ESRD.

Although the clinical manifestations of the declining GFR2 per se dominate the clinical presentation in all forms of CRD1, in many cases the underlying etiology can be presumed from associated additional clinical information (Table 261-3).

GENETIC CONSIDERATIONS

Disorders with clear-cut monogenic inheritance comprise a small but important component among the etiologies of CRD1. Among these, autosomal dominant polycystic kidney disease is the most common on a world-wide basis (Chap. 265). Alport's hereditary nephritis (Chap. 264) is a less common cause of both benign hematuria without progression to CRD and more severe nephron injury with progression to ESRD4, and it most often displays an X-linked pattern of inheritance. Several genetic loci have been identified that encode important components of the glomerular podocyte-associated filtration barrier, and mutations in these genes cause inherited forms of focal segmental glomerular sclerosis with glucocorticoid nonresponsive nephrotic syndrome and progression to ESRD. Nephronopthisis, medullary cystic kidney disease, and Fabry's disease are among other rare causes of progressive CRD with monogenic inheritance based on well-characterized genetic loci. In contrast, the two most common etiologies of CRD, diabetes mellitus (both types 1 and 2) and essential hypertension, display complex polygenic patterns of inheritance.

The striking interindividual variability in the rate of progression to ESRD5 has an important heritable component, and a number of genetic loci that contribute to the progression of CRD1 have been identified. Most extensively studied has been an insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene. The homozygous deletion (D/D) variant is associated with the highest expression of endogenous ACE activity and a greater risk of CRD progression. This finding leads to the prediction that ACE inhibitor therapy might be most effective in patients who are homozygous for the "at-risk" allele. Similar conclusions have been reached with respect to genes encoding other components of the renin-angiotensin axis. More recent studies of genetic association with renal failure progression have focused on a region of human chromosome 10, homologous to a well-characterized rodent renal failure susceptibility gene (Rf1).

PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA

Azotemia refers to the retention of nitrogenous waste products as renal insufficiency develops. Uremia refers to the more advanced stages of progressive renal insufficiency when the complex, multiorgan system derangements become clinically manifest.

Although not the major cause of overt uremic toxicity, urea may contribute to some of the clinical abnormalities, including anorexia, malaise, vomiting, and headache. Additional categories of nitrogenous excretory products include guanido compounds, urates and hippurates, end products of nucleic acid metabolism, polyamines, myoinositol, phenols, benzoates, and indoles, among others. Nitrogenous compounds with a molecular mass of 500 to 12,000 Da (so-called middle molecules) are also retained in CRD1 and similarly are believed to contribute to morbidity and mortality in uremic subjects. However, uremia involves more than renal excretory failure alone. A host of metabolic and endocrine functions normally subserved by the kidney are also impaired, resulting in anemia; malnutrition; impaired metabolism of carbohydrates, fats, and proteins; defective utilization of energy; and metabolic bone disease. Furthermore, plasma levels of many polypeptide hormones, including parathyroid hormone (PTH), insulin, glucagon, luteinizing hormone, and prolactin, rise with renal failure, not only because of impaired renal catabolism but also because of enhanced endocrine secretion, occurring as a secondary consequence of primary excretory or synthetic renal dysfynction. On the other hand, the renal production of erythropoietin (EPO) and 1,25-dihydroxycholecalciferol is impaired. Thus, the pathophysiology of the uremic syndrome can be divided into two sets of abnormalities: (1) those consequent to the accumulation of products of protein metabolism; and (2) those consequent to the loss of other renal functions, such as fluid and electrolyte homeostasis and hormonal abnormalities.

CLINICAL AND LABORATORY MANIFESTATIONS OF CHRONIC RENAL FAILURE AND UREMIA

Uremia leads to disturbances in the function of every organ system. Chronic dialysis (Chap. 262) reduces the incidence and severity of these disturbances, so that, where modern medicine is practiced, the overt and florid manifestations of uremia have largely disappeared. Unfortunately, as indicated in Table 261-4, even optimal dialysis therapy is not a panacea, because some disturbances resulting from impaired renal function fail to respond fully, while others continue to progress.

FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS (SEE ALSO CHAPS. 41, 42, AND 259)

Sodium and Water Homeostasis In most patients with stable CRD1, the total body contents of Na+ and H2O are increased modestly, although this may not be clinically apparent. The underlying etiologic disease process may itself disrupt glomerulotubular balance and promote Na+ retention (e.g., glomerulonephitis), or excessive Na+ ingestion may lead to cumulative positive Na+ balance and attendant extracellular fluid volume (ECFV) expansion. Such ECFV expansion contributes to hypertension, which in turn accelerates further the progression of nephron injury. As long as water intake does not exceed the capacity for free water clearance, the ECFV expansion will be isotonic and the patient will remain normonatremic. Hyponatremia is an uncommon complication in predialysis patients, and water restriction is only necessary when hyponatremia is documented. Weight gain usually associated with volume expansion may be offset in patients with CRD by concomitant loss of lean body mass. In the CRD patient who is not yet on dialysis but has clear evidence of ECFV expansion, administration of loop diuretics coupled with restriction of salt intake are the mainstays of therapy. It should be noted that resistance to loop diuretics in renal failure often mandates use of higher doses than those usually used when GFR2 is well preserved. The combination of loop diuretics with metalozone, which inhibits the Na+Cl- cotransporter of the distal convoluted tubule, can sometimes overcome diuretic resistance. When the GFR falls to 5 to 10 mL/min per 1.73 m2, even high doses of combination diuretics are ineffective. ECFV expansion under these circumstances usually means that dialysis is indicated.

Patients with CRD1 also have impaired renal mechanisms for conserving Na+ and H2O (Chap. 259). When an extrarenal cause for fluid loss is present (e.g., vomiting, diarrhea, sweating, fever), these patients are prone to volume depletion. Depletion of ECFV6 may compromise residual renal function with resulting signs and symptoms of overt uremia. Because of impaired renal Na+ and H2O conservation, the usual indices of prerenal azotemia (oliguria, high urine osmolality, low urinary Na+ concentration, and low fractional excretion of Na+) are not useful. Cautious volume repletion, usually with normal saline, returns ECFV to normal and usually restores renal function to prior levels.

Potassium Homeostasis (See also Chap. 41) In CRD1, the decline in GFR2 is not necessarily accompanied by a concomitant and proportionate decline in urinary K+ excretion. In addition, K+ excretion in the gastrointestinal tract is augmented in patients with CRD. However, hyperkalemia may be precipitated in a number of clinical situations, including constipation, augmented dietary intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, metabolic acidosis, and following the exposure to a variety of medications that inhibit K+ entry into cells or K+ secretion in the distal nephron. Most commonly encountered medications in this regard are beta blockers, ACE7 inhibitors and angiotensin receptor blockers, K+-sparing diuretics (amiloride, triamterene, spironolactone), and nonsteroidal anti-inflammatory drugs (NSAIDs). In addition, certain etiologies of CRD may be associated with earlier and more severe disruption of K+ secretory mechanisms in the distal nephron, relative to the reduction in GFR. Most important are conditions associated with hyporeninemic hypoaldosteronism (e.g., diabetic nephropathy and certain forms of distal renal tubular acidosis; Chaps. 264 and 265).

Hypokalemia is uncommon in CRD1 and usually reflects markedly reduced dietary K+ intake, in association with excessive diuretic therapy or gastrointestinal losses. Hypokalemia occurs as a result of primary renal K+ wasting in association with other solute transport abnormalities, as in Fanconi's syndrome, renal tubular acidosis, or other forms of hereditary or acquired tubulointerstitial diseases. However, even under these circumstances, as GFR2 declines, the tendency to hypokalemia diminishes and hyperkalemia may supervene. Accordingly, K+ supplementation and K+-sparing diuretics should generally be avoided as GFR declines.

Metabolic Acidosis (See also Chap. 42) Acidosis is a common disturbance during the advanced stages of CRD1. Although in a majority of patients with CRD the urine can be acidified normally, these patients have a reduced ability to produce ammonia. Hyperkalemia further depresses urinary ammonium excretion. The combination of hyperkalemia and hyperchloremic metabolic acidosis (known as type IV renal tubular acidosis, or hyporeninemic hypoaldosteronism) is most characteristically seen in patients with diabetes or in those with predominantly tubulointerstitial disease. Treatment of the hyperkalemia frequently improves the acidosis as well.

With advancing renal failure, total urinary net daily acid excretion is usually limited to 30 to 40 mmol, and an anion gap of ~20 mmol/L with a reciprocal fall in plasma [HCO3-] may develop. In most patients, the metabolic acidosis is mild; the pH is rarely 7.35 and can usually be corrected by treating the patient with 20 to 30 mmol of NaHCO3 or sodium citrate daily. However, the concomitant Na+ load mandates careful attention to volume status and the potential need for diuretic agents. Also, citrate enhances aluminum absorption in the large bowel, and citrate-containing agents should be avoided if aluminum-containing drugs are also administered. Severe symptomatic manifestations of acid-base imbalance may occur when the patient is challenged with an excessive endogenous or exogenous acid load or loses excessive alkali (e.g., with diarrhea).

TREATMENT

Adjustments in dietary intake and use of loop diuretics, occasionally in combination with metalozone, may be needed to maintain salt and hence extracellular fluid volume balance. In contrast, overzealous salt restriction and diuretic use may cause hypovolemia and precipitate a further decline in GFR2. Occasional patients with salt-wasting states need to be given sodium-rich diets or sodium supplements. Water restriction is indicated only if there is a demonstrated propensity to hyponatremia. Intractable ECFV8 expansion, despite dietary restriction and diuretic use, indicates the need to initiate renal replacement therapy. Hyperkalemia often responds to dietary restriction of potassium, avoidance of potassium-containing or -retaining medications, and to the use of diuretics if they are also indicated for management of sodium balance. Many salt substitutes contain potassium instead of sodium, and patients with CRD1 seeking to avoid sodium should be cautioned accordingly as part of their dietary counseling. Potassium-binding resins taken with cathartics can promote gastrointestinal potassium losses and thus are useful as temporizing measures in the treatment or avoidance of hyperkalemia in CRD patients. However, the need for such treatment over a prolonged period, in the absence of other reversible causes of hyperkalemia, usually signifies the need to initiate renal replacement therapy.

BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM (FIG. 261-1; SEE ALSO CHAPS. 331 AND 332)

The major disorders of bone disease in CRD1 can be classified into those associated with high bone turnover and high PTH9 levels (including osteitis fibrosa, the hallmark lesion of secondary hyperparathyroidism) and low bone turnover with low or normal PTH levels (osteomalacia and adynamic bone disease).

The pathophysiology of bone disease due to secondary hyperparathyroidism is related to abnormal mineral metabolism. (1) Decreased GFR2 leads to reduced inorganic phosphate (PO43-) excretion and consequent PO43- retention, (2) retained PO43- has a direct stimulatory effect on PTH9 synthesis and on cellular mass of the parathyroid glands, (3) retained PO43- also indirectly causes excessive production and secretion of PTH through lowering of ionized Ca2+ and by suppression of calcitriol (1,25-dihydroxycholecalciferol) production, and (4) reduced calcitriol production in CRD1 results both from decreased synthesis due to reduced kidney mass and from hyperphosphatemia. Low calcitriol levels, in turn, lead to hyperparathyroidism via both direct and indirect mechanisms. Calcitriol is known to have a direct suppressive effect on PTH transcription (i.e., a genomic effect), and therefore reduced calcitriol in CRD causes elevated levels of PTH. In addition, reduced calcitriol leads to impaired Ca2+ absorption from the gastrointestinal tract, thereby leading to hypocalcemia, which then increases PTH secretion and production. Taken together, hyperphosphatemia, hypocalcemia, and reduced calcitriol synthesis all promote the production of PTH and the proliferation of parathyroid cells, resulting in secondary hyperparathyroidism.

In addition to excessive release of PTH9 from individual parathyroid cells, the mass of parathyroid cells increases progressively with CRD1. Excessive parathyroid gland cellular mass may assume one of the following patterns: (1) diffuse hyperplasia (polyclonal), (2) nodular growth (monoclonal) within diffuse hyperplastic tissue, or (3) diffuse monoclonal hyperplasia ("adenoma" or tertiary autonomous hyperparathyroidism). Patients with monoclonal ("autonomous") hyperplasia are especially prone to develop hypercalcemia following successful kidney transplantation, often necessitating parathyroidectomy. High PTH levels stimulate osteoblasts and result in high bone turnover, which leads to osteitis fibrosa cystica. The latter is characterized by irregularly woven abnormal osteoid, fibrosis, and cyst formation, which result in decreased cortical bone and bone strength and an increased risk of fracture.

Low-turnover bone disease can be classified into two categories — osteomalalcia and adynamic bone disease. Both lesions are characterized by a reduced number of osteoclasts and osteoblasts and decreased activity of the latter. In osteomalacia there is an accumulation of unmineralized bone matrix, or increased osteoid volume, which may be caused by vitamin D deficiency, excess aluminum deposition, or metabolic acidosis. Adynamic bone disease is now recognized to be as prevalent as the hyperparathyroid bone lesion in patients with CRD1 and ESRD10, and is especially common among diabetic patients. Adynamic bone disease is characterized by reduced bone volume and mineralization and may result in part from excessive suppression of PTH9 production with calcitriol treatment or, currently less common, from aluminium exposure.

Irrespective of the cause for skeletal abnormalities in CRD1, bone disease can lead to pain, increased incidence of fractures, and severe incapacity. Bone fractures complicate both the high- and low-turnover types of bone disease, and it is now appreciated that patients with adynamic bone may be more predisposed to fractures than those with osteitis fibrosa cystica. In the latter disorder, however, a PTH9-associated proximal myopathy often coexists, giving rise to gait abnormalities and impaired ambulation.

Other Complications of Abnormal Calcium-Phosphate Product Metabolism In addition to abnormalities in bone metabolism, abnormal calcium-phosphate product metabolism may lead to calciphylaxis, i.e., extraosseous ("metastatic") calcification of soft tissue and blood vessels. Electron beam computed tomography in patients with CRD1 has revealed highly elevated coronary calcification scores, which likely represent a major factor in the predisposition to occlusive coronary vascular disease in the CRD and ESRD11 populations. The pathogenesis remains unclear, but hyperphosphatemia, hypercalcemia, elevated calcium-phosphate product, and increased PTH9 levels are all thought to contribute to this process. Calciphylaxis represents a severe and systemic form of vascular and soft tissue calcium-phosphate product deposition associated with skin and soft tissue necrosis, which can lead to extremity loss.

TREATMENT

Secondary hyperparathyroidism and osteitis fibrosa are best prevented and treated by reducing the plasma PO43- concentration through the use of a phosphate-restricted diet as well as oral phosphate-binding agents. Calcium carbonate and calcium acetate are useful phosphate-binding agents. Sevelamer, a nonabsorbable, non-calcium-containing polymer has been recently added to the phosphate-lowering armamentarium. It has an advantage over the calcium-based phosphate chelating agents in that it does not predispose CRD1 patients to hypercalcemia and attenuates calcium deposition in the coronary arteries and aorta.

Daily oral calcitriol, or intermittent oral or intravenous pulses, appears to exert a direct suppressive effect on PTH9 secretion, in addition to the indirect effect mediated through raising plasma Ca2+ concentration. The use of calcitriol and calcium preparations in the predialysis population must take into account potential effects of increased PO43- and Ca2+ on the rate of progression of CRD1. The recommended target plasma PO43- concentration is approximately 1.4 mmol/L (4.5 mg/dL), with a corresponding plasma Ca2+ concentration of approximately 2.5 mmol/L (10 mg/dL) in an attempt to suppress parathyroid hyperplasia, thus avoiding or reversing osteitis fibrosa cystica, osteomalacia, and myopathy. It is particularly important to maintain the calcium-phosphate product in the normal range to avoid metastatic calcification. Recognition of the role of the extracellular calcium-sensing receptor has led to the development of calcimimetic agents that enhance the sensitivity to Ca2+-suppressive effects on PTH secretion. The first-generation calcimimetic agent tested produced a dose-dependent reduction in PTH and plasma Ca2+ concentration, and subsequent formulations with improved pharmacokinetic profiles show great promise as effective and safe treatments for secondary hyperparathyroidism. However, since adynamic bone disease is often a consequence of overzealous treatment of secondary hyperparathyroidism, suppression of PTH levels to 120 pg/mL in CRD patients may not be desirable.

The incidence of aluminum-induced osteomalacia has been greatly reduced with the recognition of aluminum as the principal culprit. Therapy for this disorder is based on the complete cessation of the use of aluminum combined with the use of a chelating agent such as deferoxamine.

Management of metabolic acidosis should aim to maintain a nearly normal level of plasma bicarbonate with the administration of calcium acetate or calcium carbonate, with the addition of sodium bicarbonate (limited by considerations of sodium load) if necessary. Excessive administration of alkali should be avoided to minimize risk of urinary precipitation of Ca2+ phosphate.

CARDIOVASCULAR ABNORMALITIES

Cardiovascular disease is the leading cause of morbidity and mortality in patients with CRD1 at all stages. Estimates of the increase in cardiovascular disease risk attributable to CRD range from 10- to 200-fold, depending on the stage of CRD, other risk factors, and comorbid conditions. Between 30 and 45% of patients reaching ESRD12 already have advanced cardiovascular complications. Thus the management of patients with CRD should emphasize prevention of cardiovascular complications as well as measures aimed at alleviating the progression and complications of CRD itself.

Ischemic Cardiovascular Disease CRD1 at all stages constitutes a major risk factor for ischemic cardiovascular disease, including occlusive coronary heart, cerebrovascular, and peripheral vascular diseases. Increased prevalence of coronary heart disease in CRD derives from both traditional ("classic") and CRD-related ("nontraditional") risk factors. The former include hypertension (see below), hypervolemia, dyslipidemia, sympathetic overactivitiy, and hyperhomocysteinemia. The CRD-related risks include anemia, hyperphosphatemia, hyperparathyroidism, and a state of "microinflammation" that can be found at all stages of CRD but is undoubtedly aggravated by dialysis. The inflammatory state elicits a rise in acute-phase reactants such as interleukin 6 and C-reactive protein, which contribute to the coronary occlusive process and are predictors of cardiovascular disease risk. Other abnormalities augment myocardial ischemia. These include reduced myocardial tolerance to ischemia due to left ventricular hypertrophy (see below) and microvascular disease. Also, coronary reserve, defined as the increase in coronary blood flow in response to greater demand, is attenuated. Nitric oxide is an important mediator for vascular dilatation. Its availability in CRD is decreased because of increased concentrations of asymmetric dimethyl-l-arginine, even at early stages of CRD, and also because nitric oxide is scavenged by reactive oxygen species. In addition, coronary arteriolar hypertrophy/hyperplasia limits vasodilatory capacity.

Congestive Heart Failure (See also Chap. 216) Abnormal cardiac function secondary to myocardial ischemic disease and/or left ventricular hypertrophy, together with salt and water retention in uremia, often result in congestive heart failure and/or pulmonary edema. A unique form of pulmonary congestion and edema may occur even in the absence of volume overload and is associated with normal or mildly elevated intracardiac and pulmonary capillary wedge pressures. This entity, characterized radiologically by peripheral vascular congestion giving rise to a "butterfly wing" distribution, is due to increased permeability of alveolar capillary membranes. This "low-pressure" pulmonary edema as well as cardiopulmonary abnormalities associated with circulatory overload usually respond promptly to vigorous dialysis.

Hypertension and Left Ventricular Hypertrophy (See also Chap. 230) Hypertension is the most common complication of CRD1 and ESRD13. It may develop early during the course of CRD and is associated with adverse outcomes — in particular, more rapid loss of renal function and development of cardiovascular disease. Numerous epidemiologic studies and clinical trials have shown a relationship between the level of blood pressure and rate of progression of diabetic and non-diabetic kidney disease (see below).

Administration of EPO14 (p. 1658) may raise blood pressure and increase the requirement for antihypertensive drugs in CRD1 patients. Left ventricular hypertrophy and dilated cardiomyopathy are among the most ominous risk factors for excess cardiovascular morbidity and mortality in patients with CRD and ESRD15 and are thought to be related primarily to prolonged hypertension and ECFV16 overload. In addition, anemia and the surgical placement of an arteriovenous anastomosis for future or ongoing dialysis access may generate a high cardiac output state and pulmonary hypertension, which also intensify the burden placed on the left ventricle. Absence of hypertension may signify the presence of a salt-wasting form of renal disease (e.g., medullary cystic disease, chronic tubulointerstitial disease, or papillary necrosis), ongoing antihypertensive therapy, volume-depletion due to gastrointestinal causes or diuretic therapy, or reduced cardiac index.

Since volume overload is the major cause of hypertension in uremia, the normotensive state can often be restored by appropriate (not overzealous) use of salt restriction and natriuretic drugs or ultrafiltration in the dialysis setting. Nevertheless, because of hyperreninemia and other disturbances in renal vasoconstrictors and vasodilators, some patients remain hypertensive despite rigorous salt and water restriction and ultrafiltration. Rarely, such patients may develop accelerated or malignant hypertension. Intravenous labetolol, or more recently approved agents such as fenoldopam or urapidil, together with control of ECFV17 generally control such hypertension. Enalaprilat or other ACE18 inhibitors may also be considered, but in the face of bilateral renovascular disease they have the potential to further reduce GFR2 abruptly.

TREATMENT

Management of Hypertension (See also Chap. 230) There are two overall goals: to slow the progression of CRD1 itself and to prevent the extrarenal complications of hypertension, such as cardiovascular disease and stroke. In all patients with CRD, blood pressure should be controlled to at least the level established in the guidelines of the Sixth Joint National Commission on Hypertension Detection Education and Follow-up Program (130/80 to 85 mmHg). In CRD patients with diabetes or proteinuria 1 g per 24 h, blood pressure should be further reduced to 125/75 mmHg. Volume control with salt restriction and diuretics is the mainstay of therapy. When volume management is not sufficient, the choice of antihypertensive agent is similar to that in the general population, with the added consideration of cardioprotective benefit provided by ACE19 inhibition, or angiotensin receptor blockade. The choice of antihypertensive agents may come from all the major classes, with careful consideration of comorbid conditions. However, powerful direct-acting vasodilators, such as hydralazine or minoxidil, may perpetuate the tendency to cardiac hypertrophy, despite the lowering of blood pressure. Therefore, prolonged use of such agents should be reserved for those very rare patients in whom severe refractory hypertension persists, despite adequate volume reduction and compliance with all other classes of antihypertensives.

Management of Cardiovascular Disease Hypertension, hyperhomocysteinemia, and lipid abnormalities promote atherosclerosis but are potentially treatable complications of CRD1. Ongoing or prior nephrotic syndrome is also associated with hyperlipidemia and hypercoagulability, which increase the risk of occlusive vascular disease. Since diabetes mellitus and hypertension are themselves the two most frequent etiologies of CRD, it is not surprising that cardiovascular disease is the most frequent cause of death in ESRD20 patients. Therefore, accepted life-style changes and therapeutic measures for cardiac risk reduction (Chap. 225) are especially important in this group of patients. Hyperhomocysteinemia may respond to vitamin therapy, which includes folate supplementation to between 1 and 5 mg/d. Hyperlipidemia in patients with CRD and ESRD should be managed aggressively according to the guidelines of the National Cholesterol Education Program (Chap. 335). If dietary measures are inadequate, the preferred lipid-lowering medications are gemfibrozil and an HMG-CoA reductase inhibitor. However, caution should be exercised in combining these two classes of agents because of an increased risk of myositis and rhabdomyolysis in CRD and ESRD patients.

Pericarditis (See also Chap. 222) With the advent of early initiation of renal replacement therapy, pericarditis is now observed more often in underdialyzed patients than in predialysis CRD1 patients. Pericardial pain with respiratory accentuation, accompanied by a friction rub, are the hallmarks of uremic pericarditis. The finding of a multicomponent friction rub strongly supports the diagnosis. Classic electrocardiographic abnormalities include PR-interval depression and diffuse ST-segment elevation. Pericarditis may be accompanied by the accumulation of pericardial fluid that is readily detected by echocardiography and that sometimes leads to cardiac tamponade. Pericardial fluid in uremic pericarditis is more often hemorrhagic than in viral pericarditis.

TREATMENT

Uremic pericarditis is an absolute indication for initiation of dialysis or for intensification of the dialysis prescription in those already on dialysis. Because of the propensity to hemorrhagic pericardial fluid, heparin-free dialysis is indicated. Pericardiectomy should be considered only if more conservative measures fail. Nonuremic causes of pericarditis and pericardial effusion include viral, malignant, and tuberculous pericarditis and pericarditis associated with myocardial infarction; these are also more frequent in patients with ESRD21 and should be managed according to the dictates of the underlying disease process.

HEMATOLOGIC ABNORMALITIES

Anemia A normocytic, normochromic anemia attributable to CRD1 is observed beginning at stage 3 CRD and is almost universal at stage 4. If untreated, the anemia of CRD is associated with a number of physiologic abnormalities, including decreased tissue oxygen delivery and utilization, increased cardiac output, cardiac enlargement, ventricular hypertrophy, angina, congestive heart failure, decreased cognition and mental acuity, altered menstrual cycles, and impaired host defense against infection. In addition, anemia may play a role in growth retardation in children with CRD. The primary cause of anemia in patients with CRD is insufficient production of EPO22 by the diseased kidneys. Additional factors include iron and folate deficiency, severe hyperparathyroidism, acute and chronic inflammation, aluminum toxicity, shortened red cell survival, and associated comorbid conditions such as hemoglobinopathies. These potential contributing factors should be considered and addressed, especially in EPO-resistant patients.

TREATMENT

The anemia of CRD1 is due to several factors including chronic blood loss, hemolysis, marrow suppression by retained uremic factors and reduced renal production of EPO23. The availability of recombinant human EPO, epoetin alfa, has made possible one of the most significant advances in the care of renal patients since the introduction of dialysis and transplantation. More recently, a novel erythropoiesis-stimulating protein has been introduced for the treatment of anemia in CRD patients. This protein, darbopoetin alfa, is a hyperglycosylated analogue of recombinant human EPO that possesses greater biologic activity and prolonged half-life. Thus, dose intervals can be extended and still effectively correct renal anemia in both predialysis and dialysis patients. Guidelines for using epoetin and darbopoetin alfa for the management of anemia of CRD are provided in Table 261-5.

The iron status of the patient with CRD1 must be assessed, and adequate iron stores should be available before treatment with EPO24 is initiated. Iron supplementation is usually essential to ensure an adequate response to EPO in patients with CRD, because the demands for iron by the erythroid marrow frequently exceed the amount of iron that is immediately available for erythropoiesis (as measured by percent transferrin saturation) as well as iron stores (as measured by serum ferritin). In most cases, intravenous iron is required to achieve and/or maintain adequate iron. However, excessive iron therapy may be associated with a number of complications, including hemosiderosis, accelerated atherosclerosis, increased susceptibility to infection, and possibly an increased propensity to the emergence of malignancies. In addition to iron, an adequate supply of the other major substrates and cofactors for erythrocyte production must be assured, especially vitamin B12 and folate. Anemia resistant to recommended doses of EPO in the face of adequate availability of iron and vitamin factors often suggests inadequate dialysis; uncontrolled hyperparathyroidism; aluminum toxicity; chronic blood loss or hemolysis; associated hemoglobinopathy, malnutrition, chronic infection, multiple myeloma, or another malignancy. Blood transfusions may contribute to suppression of erythropoiesis in CRD; because they increase the risk of hepatitis, hemosiderosis, and transplant sensitization, they should be avoided unless the anemia fails to respond to erythropoietin and the patient is symptomatic.

Abnormal Hemostasis This is common in CRD1 and is associated with prolongation of bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption. Clinical manifestations include an increased tendency to abnormal bleeding and bruising; bleeding from surgical wounds; and spontaneous bleeding into the gastrointestinal tract, pericardial sac, or intracranial vault (in the form of subdural hematoma or intracerebral hemorrhage). Notwithstanding these abnormalities in hemostasis, CRD patients have a greater susceptibility to thromboembolic complications, particularly if their underlying disease was characterized by a nephrotic presentation.

TREATMENT

Abnormal bleeding times and coagulopathy in patients with renal failure may be reversed with desmopressin, cryoprecipitate, conjugated estrogens, and blood transfusions, as well as EPO25. On the other hand, patients with CRD1 should also be viewed as being at greater risk for thromboembolic complications and receive appropriate anticoagulant prophylaxis when indicated. Avoidance or dose adjustment of certain anticoagulants, such as fractionated low-molecular-weight heparin, is necessary in CRD patients.

NEUROMUSCULAR ABNORMALITIES

Central, peripheral, and autonomic neuropathy, as well as abnormalities in muscle composition and function, are all common complications in CRD1. Retained nitrogenous metabolites and middle molecules as well as PTH9 all contribute to the pathophysiology of neuromuscular abnormalities. Subtle clinical manifestations of uremic neuromuscular disease usually become evident beginning at stage 3 CRD. Early manifestations of central nervous system complications include mild disturbances in memory and concentration and sleep disturbance. Neuromuscular irritability, including hiccups, cramps, and fasciculations/twitching of muscles, becomes evident at later stages. Asterixis, myoclonus, and chorea are common in terminal uremia, which may also be associated with seizures and coma.

Peripheral neuropathy usually becomes clinically evident when the patient has been at stage 4 CRD1 for 6 months, although electrophysiologic and histologic evidence of peripheral neuropathy occurs earlier. Initially, sensory nerves are involved more than motor nerves, lower extremities more than upper, and distal portions of the extremities more than proximal. The "restless legs syndrome" is characterized by ill-defined sensations of discomfort in the legs and feet requiring frequent leg movement. If dialysis is not instituted soon after onset of sensory abnormalities, motor involvement follows, including muscle weakness and loss of deep tendon reflexes. Accordingly, evidence of peripheral neuropathy is a firm indication for renal replacement therapy. Some of the central nervous system and neuromuscular complications of advanced uremia resolve with dialysis, although nonspecific electroencephalographic abnormalities may persist. Successful transplantation may reverse residual peripheral neuropathy.

GASTROINTESTINAL AND NUTRITIONAL ABNORMALITIES

Uremic fetor, a uriniferous odor to the breath, derives from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste sensation. Gastritis, peptic disease, and mucosal ulcerations at any level of the gastrointestinal tract occur in uremic patients and can lead to abdominal pain, nausea, vomiting, and blood loss. Other gastrointestinal complications of CRD1 include an increased incidence of diverticulosis, particularly in patients with polycystic kidney disease, and an increased incidence of pancreatitis. In addition, central nervous system effects of uremia contribute to anorexia, hiccups, nausea, and vomiting. Protein restriction is useful in diminishing nausea and vomiting late in the course of renal failure. However, protein restriction should not be implemented in patients with signs of protein-energy malnutrition, which is a consequence of low protein and caloric intake, resistance to anabolic actions of insulin and other hormones and growth factors, disturbed dietary protein utilization, proinflammatory cytokine activation, and metabolic acidosis. Assessment for protein-energy malnutrition should begin at stage 3 CRD (GFR2 60 mL/min per 1.73 m2). A number of indices are useful in this assessment and include dietary history, edema-free body weight, measurement of urinary protein nitrogen appearance, and plasma markers, of which albumin is the most useful. Guidelines for calorie and protein intake in patients with CRD are provided below (p. 1661).

ENDOCRINE-METABOLIC DISTURBANCES

Disturbances in parathyroid function have already been considered (p. 1656).

Glucose metabolism is impaired in CRD1, as evidenced by a slowing of the rate at which blood glucose levels decline after a glucose load. Fasting blood glucose is usually normal or only slightly elevated, and the mild glucose intolerance related to uremia per se, when present, does not require specific therapy. Because the kidney contributes significantly to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic subjects, both in the fasting and postprandial states. However, the response to insulin and glucose utilization is impaired in CRD. Many hypoglycemic drugs require dose reduction in renal failure, and some, such as metformin, are contraindicated when the GFR2 has diminished by more than approximately 25 to 50%.

In women, estrogen levels are low, and amenorrhea and inability to carry pregnancies to term are common manifestations of uremia. When the GFR2 has declined by ~30%, pregnancy may hasten the progression of CRD1. In men with CRD, including those receiving chronic dialysis, impotence, oligospermia, and germinal cell dysplasia are common, as are reduced plasma testosterone levels. Like growth, sexual maturation is often impaired in adolescent children with CRD, even among those treated with chronic dialysis. Many of these abnormalities improve or reverse with successful renal transplantation.

DERMATOLOGIC ABNORMALITIES

The skin may show evidence of anemia (pallor), defective hemostasis (ecchymoses and hematomas), calcium-phosphate deposition and secondary hyperparathyroidism (pruritus, excoriations), and deposition of pigmented metabolites or urochromes (yellow discoloration) or urea itself (uremic frost). Although many of these cutaneous abnormalities improve with dialysis, uremic pruritus often remains a problem. The first lines of management are to rule out unrelated skin disorders and to control PO43-concentration with avoidance of an elevated calcium-phosphate product. Occasionally, pruritus remains refractory to these measures and to other nonspecific systemic and topical therapies. Skin necrosis can occur as part of the calciphylaxis syndrome, which also includes subcutaneous, vascular, joint, and visceral calcification in patients with poorly controlled calcium-phosphate product.

EVALUATION AND MANAGEMENT OF PATIENTS WITH CRD

INITIAL APPROACH

History and Physical Examination Complaints referred to the kidneys themselves are often conspicuously absent in CRD1, and this often surprises patients and is a cause of skepticism and denial. Of special importance in establishing the etiology of CRD are a history of hypertension; diabetes; systemic infectious, inflammatory, or metabolic diseases; exposure to drugs and toxins; and a family history of renal and urologic disease. Drugs of particular importance include analgesics (usage frequently underestimated or denied by the patient), NSAIDs26, gold, penicillamine, antimicrobials, lithium, and ACE27 inhibitors. In evaluating the uremic syndrome, questions about appetite, diet, nausea, vomiting, hiccupping, shortness of breath, edema, weight change, muscle cramps, pruritus, mental acuity, and activities of daily living are especially helpful.

On physical examination, particular attention should be paid to blood pressure, fundoscopy, precordial examination, examination of the abdomen for bruits and palpable renal masses, examination for edema, and neurologic examination for the presence of asterixis, muscle weakness, and neuropathy. In addition the evaluation of prostate size in men, and potential pelvic masses in women should be undertaken.

Laboratory Investigations These should also focus on a search for clues to an underlying disease process and its continued activity. Therefore, if the history and physical examination warrant, immunologic tests for systemic lupus erythematosus and vasculitis might be considered. Serum and urinary protein electrophoresis should be undertaken in all patients 40 years with unexplained CRD1 and anemia, to rule out paraproteinemia. Other tests to determine the stage and chronicity of the disease, including complications of the uremic syndrome, include serial measurements of plasma creatinine and estimation of GFR2, urea, electrolytes (including HCO3-, Ca2+, and PO43-), and alkaline phosphatase to assess metabolic bone disease as well as hemoglobin. Urinalysis may be helpful in assessing the presence of ongoing activity of the underlying inflammatory or proteinuric disease process and, when indicated, should be supplemented by a 24-h urine collection for protein excretion. The latter is particularly helpful in guiding management strategies aimed at ameliorating the progression of CRD. The presence of broad casts on examination of the urinary sediment is a nonspecific finding seen with all underlying etiologies and reflects chronic tubulointerstitial scarring and tubular atrophy with widened tubule diameter, usually signifying an advanced stage of CRD.

Imaging Studies The most useful imaging study is renal ultrasonography. An ultrasound examination of the kidneys can verify the presence of two symmetric kidneys, provide an estimate of kidney size, and rule out renal masses and obstructive uropathy. The documentation of symmetric small kidneys supports the diagnosis of progressive CRD1 with an irreversible component of scarring. Normal kidney size suggests the possibility of an acute rather than chronic process. However, polycystic kidney disease, amyloidosis, diabetes, and HIV-associated renal disease (Chap. 173) may lead to CRD with normal kidney size. Documentation of asymmetric kidney size suggests either a unilateral developmental abnormality or chronic renovascular disease. In the latter case, a vascular imaging procedure, such as duplex doppler sonography of the renal arteries, radionuclide scintigraphy, or magnetic resonance angiography should be strongly considered if the possibility of revascularization is feasible. A spiral computed tomographic scan without contrast may be useful in assessing kidney stone activity. Voiding cystourethrography to rule out reflux may be indicated in some patients with a history of enuresis or with a family history of reflux. However, in most cases by the time CRD is established, reflux has resolved, and even if present, its repair does not stabilize renal function. In any case, imaging studies should avoid exposure to intravenous radiocontrast dye where possible because of its nephrotoxicity.

Renal Biopsy This procedure should be reserved for patients with near-normal kidney size, in whom a clear-cut diagnosis cannot be made by less invasive means and when the possibility of a reversible underlying disease process remains tenable, such that clarification of the underlying etiology may alter management. The extent of tubulointerstitial scarring on kidney biopsy generally provides the most reliable pathologic correlate indicating prognosis for continued deterioration toward ESRD28. Contraindications to renal biopsy include bilateral small kidneys, polycystic kidney disease, uncontrolled hypertension, urinary tract or perinephric infection, bleeding diathesis, respiratory distress, and morbid obesity. Ultrasound-guided percutaneous biopsy is the favored approach, but surgical approaches, including laparoscopic biopsy, may be considered in special circumstances such as biopsy of a solitary kidney.

ESTABLISHING THE DIAGNOSIS AND ETIOLOGY OF CRD

The most important initial step in the evaluation of a patient presenting de novo with biochemical or clinical evidence of renal failure is to distinguish newly diagnosed CRD1 from acute renal failure. Availability of past medical records documenting serial measurements of the plasma urea and/or creatinine concentrations can be of great help in this regard. In the absence of such information, some of the laboratory tests and imaging studies outlined above can be useful. In particular, a urinary sediment that is inactive or reveals proteinuria and broad casts; the demonstration of evidence of chronic metabolic bone disease with hyperphosphatemia, hypocalcemia, elevated PTH9 levels, and radiologic bone disease; normocytic and normochromic anemia; and the finding of bilaterally reduced kidney size ( 8.5 cm) by imaging studies, strongly favor a long-standing process consistent with CRD. However, these findings do not rule out the superimposition of an acute and reversible exacerbating factor that may have accelerated the decline in GFR2 (see below).

In the early stages of CRD1 it is often possible to establish the underlying etiology. Integration of a particular constellation of clinical, laboratory, and imaging findings based on the approach noted above strongly supports a particular presumed underlying etiologic disease process. For example, in a patient with insulin-dependent type 1 diabetes mellitus of 15 to 20 years duration, diabetic retinopathy, and nephrotic-range albuminuria without hematuria, the diagnosis of diabetic nephropathy is likely. The diagnosis of chronic hypertensive nephrosclerosis requires a history of long-standing hypertension, in the absence of evidence for another renal disease process, and hence it is usually a diagnosis of exclusion. Usually proteinura is mild to moderate ( 3 g/d) and the urine sediment inactive. It should be noted that in many cases of presumed hypertensive nephrosclerosis, renovascular disease not only may be the cause of hypertension but also may cause ischemic renal damage. In this regard, bilateral renovascular ischemic disease may be a greatly underdiagnosed cause of CRD. This is of therapeutic significance from two points of view: (1) documentation of ischemic renal disease secondary to occlusive vascular disease may prompt revascularization therapy in some subgroups of patients, with occasional stabilization and improvement in renal function; (2) renovascular ischemic disease is a contraindication to ACE29 inhibitor therapy in most cases. Analgesic-associated chronic tubulointerstitial nephropathy is also an underdiagnosed cause of CRD. Imaging studies, including computed tomography, often reveal pathognomonic features such as papillary calcification and necrosis. Under such circumstances, cessation of analgesic exposure may dramatically stabilize renal function.

In the absence of an etiologically suggestive clinical constellation, renal biopsy may be the only recourse to establish etiology in early CRD1. However, in advanced stages of CRD, definitively establishing an underlying etiology becomes less feasible and is also of less therapeutic significance.

TREATMENT

Specific treatments aimed at selected underlying etiologies of CRD1 are provided in the respective chapters describing these disease states. The optimal time for such therapy is usually well before there has been a measurable decline in baseline GFR2 and usually well before CRD is established. It is of benefit to follow and plot the rate of decline in GFR in all patients. Any acceleration in the rate of decline should prompt a search for superimposed acute processes that may lead to an acute and reversible decline in GFR in patients with CRD. These include superimposed volume depletion, accelerated and uncontrolled hypertension, urinary tract infection, superimposed obstructive uropathy (e.g., due to stone disease, papillary necrosis), nephrotoxic effect of medications (e.g., NSAIDs30) and radiocontrast agents, and reactivation or flare of the original underlying etiologic disease process.

SLOWING THE PROGRESSION OF CRD While there is great interindividual variation in the rate of decline of GFR2 in patients with CRD1, a series of therapeutic interventions should be pursued that aim to stabilize the GFR or reduce the annual rate of decline.

Protein Restriction (Table 261-6) A major goal of protein restriction in CRD1, beyond ameliorating the complications of uremia, is to slow the rate of nephron injury. This concept is based on clinical and experimental evidence demonstrating the role of protein-mediated hyperfiltration in progressive nephron injury. The effectiveness of protein restriction in slowing the progression of CRD has been shown in controlled clinical trials in patients with both diabetic and nondiabetic renal disease.

Protein restriction should be carried out in the context of an overall dietary program that optimizes nutritional status and avoids malnutrition, especially as patients near dialysis or transplantation. Metabolic and nutritional studies indicate that protein requirements for patients with CRD1 are similar to those for normal adults and are in the range of 0.6 g/kg per day. However, there is a particular requirement in patients with CRD that the composition of dietary protein be higher in essential amino acids, and that this be combined with an overall energy supply sufficient to mitigate a catabolic state. Energy requirements in the range of 35 kcal/kg per day are recommended. Fortunately, even patients with advanced CRD (GFR2 ~ 10 to 15 mL/min per 1.73 m2) are able to activate the same adaptive responses to dietary protein restriction as healthy individuals, i.e., a postprandial suppression of whole-body protein degradation and a marked inhibition of amino acid oxidation. These compensatory responses to dietary protein restriction and nutritional indices are sustained during long-term therapy.

Reducing Intraglomerular Hypertension and Proteinuria (See also p. 1657) In addition to reduction of cardiovascular disease risk, antihypertensive therapy in patients with CRD1 also aims to slow the progression of nephron injury, by ameliorating intraglomerular hypertension and hypertrophy. Progressive renal injury in CRD appears to be most closely related to the height of intraglomerular pressure and/or the extent of glomerular hypertrophy. Control of hypertension is as at least as important as dietary protein restriction in slowing the progression of CRD. Furthermore, the target for pharmacologic therapy is highly dependent on the level of proteinuria. Indeed, proteinuria is now considered a risk factor for both progressive nephron injury as well cardiovascular disease. Elevated blood pressure increases proteinuria due to the transmission to the glomeruli of the elevated systemic pressure. Conversely, the renoprotective effect of antihypertensive medications is evident through the curtailment of proteinuria. Thus, the more effective a given treatment is in lowering proteinuria, the greater the subsequent impact on protection from GFR2 decline. This is the basis for the treatment guideline establishing 125/75 mmHg as the target blood pressure value in proteinuric CRD patients.

Owing to their unique effect on the glomerular microcirculation (i.e., dilatation of the efferent arteriole), which is related to inhibition of the renin-angiotensin system, ACE31 inhibitors and angiotensin receptor blockers are now clearly established as effective, antiproteinuric agents. Several multicenter studies have shown that these drugs are effective in slowing the progression of renal failure in patients with both diabetic and nondiabetic renal failure. The slowing in the progression of renal failure by these drugs is strongly related to their proteinuria-lowering effect. In the absence of a significant antiproteinuric response, combined treatment with both an ACE inhibitor and angiotensin receptor blocker can be tried. Contraindications to or adverse effects of the use of these classes of agents (e.g., intractable cough, anaphylaxis, hyperkalemia not controlled by dietary restriction) may prompt the choice of calcium channel blockers as a second-line therapeutic approach. Among the calcium channel blockers, diltiazem and verapamil may exhibit superior antiproteinuric and renal protective effects. Available clinical studies have indicated that calcium antagonists as a group do not adversely affect renal function in patients with nondiabetic renal insufficiency, and also indicate that they may be more effective in preventing or ameliorating progressive renal injury than some other classes of antihypertensive drugs in this group of patients. Thus, it appears that at least two different categories of responses may exist: one in which progression is strongly associated with systemic and intraglomerular hypertension and with proteinuria (e.g., diabetic nephropathy, glomerular diseases) and in which ACE inhibitors and angiotensin receptor blockers are likely to be the first choice; and the second in which proteinuria is mild or absent (e.g., adult polycystic kidney disease), probably with a less prominent role for intraglomerular hypertension, and which might respond as well to calcium entry blockers.

SLOWING DIABETIC RENAL DISEASE (SEE ALSO CHAP. 323) Diabetic nephropathy is now the leading cause of CRD1 eventuating in ESRD32 in many parts of the world. Furthermore, the prognosis of diabetic patients on chronic renal replacement therapy is very poor, owing to accelerated cardiovascular disease. Therefore, it is particularly compelling to search for strategies whose aim is to prevent or slow the progression of this complication of diabetes mellitus.

Glucose Control Although tight glycemic control reduces the risk of kidney disease in patients with type 1 diabetes, there has been prolonged controversy over whether the same is true in patients with type 2 diabetes. The results of recent controlled prospective studies provide incontrovertible evidence that in type 2 diabetes mellitus the risk of the development and progression of albuminuria and CRD1 can also be substantially reduced by improving glycemic control. The United Kingdom Prospective Diabetes Study showed that the way in which glycemic control was achieved, whether by insulin or oral antihyperglycemic agents such as sulfonylureas or metformin, was far less important than success in achieving control. Achieving a target hemoglobin A1C level of 7.2%, as compared to 9%, is associated with an approximately 50% reduction in the occurrence of indices of progressive nephropathy. As a result of these findings, recommendations for glucose control aim to achieve plasma values for preprandial glucose in the range of 90 to 130 mg/dL, and for average bedtime glucose of 110 to 150 mg/dL and hemoglobin A1C 7%. Reduction in GFR2 mandates dose adjustment of many antihyperglycemic agents, and in particular the discontinuation of metformin when the plasma creatinine is 133 umol/L (1.5 mg/dL).

Control of Blood Pressure and Proteinuria Hypertension or an abnormal circadian blood pressure profile is found in 80% of type 2 diabetic patients at the time of diagnosis. Both of these findings correlate with the presence of albuminuria and are powerful predictors of cardiovascular and renal events. The onset of microalbuminuria precedes the decline in GFR2 in diabetic patients and heralds renal as well as cardiovascular complications. Therefore, microalbuminuria testing is recommended in all diabetic patients at least annually, and more frequently to follow therapeutic interventions. Antihypertensive treatment reduces albuminuria and diminishes the risk of progression of albuminuria even in normotensive patients with diabetes. There is now compelling evidence that ACE33 inhibitors and angiotensin receptor blockers have specific renoprotective properties in diabetic patients with microalbuminuria or overt proteinuria. These salutary effects are almost certainly mediated by reducing intraglomerular pressure and inhibition of transforming growth factor ß-mediated sclerosing pathways.

MANAGING OTHER COMPLICATIONS OF CHRONIC RENAL FAILURE Impending Uremic Symptomatology Temporary relief of symptoms and signs of impending uremia, such as anorexia, nausea, vomiting, asterixis, lassitude, and other central nervous system manifestations, may be achieved with protein restriction. However, this must be associated with careful monitoring of nutritional status, so as to avoid protein-energy malnutrition, evidence of which serves as a clear-cut indication for initiation of renal replacement therapy.

Medication Dose Adjustment (See also Chap. 3) Although the loading dose of most drugs is not affected by CRD1, maintenance doses of many drugs need to be adjusted. For those drugs in which 70% excretion is by a nonrenal (e.g., hepatic or intestinal) route, dosage adjustment may not be needed. Some drugs that should be entirely avoided include meperidine, metformin, and other oral hypoglycemics with a renal route of elimination. Commonly used medications that require either a reduction in dosage or changes in interval include allopurinol, many antibiotics, several antihypertensives, and antiarrhythmics. For a comprehensive detailed and authoritative listing of the recommended dose adjustment for most of the commonly used medications, the reader is referred to the American College of Physicians' handbook "Drug Prescribing in Renal Failure" (see .org). In addition to dose adjustment requirements, many drugs have nephrotoxicity as a prominent side effect, to which patients with CRD are more susceptible. Of particular notoriety in this regard are NSAIDs34, because of their widespread availability and usage. These drugs aggravate the tendency to sodium retention, hypertension, hyperkalemia, and hyponatremia and further reduce GFR2 in patients with CRD. In this regard, there is no advantage to more selective inhibitors of cyclooxygenase-2.

Preparation for Renal Replacement Therapy (See also Chaps. 262 and 263) Over the past 40 years, renal replacement therapy using dialysis and transplantation has prolonged the lives of hundreds of thousands of patients with ESRD35. Renal replacement therapy should not be initiated when the patient is totally asymptomatic; however, dialysis and/or transplantation should be started sufficiently early to prevent serious complications of the uremic state. Clear indications for initiation of renal replacement therapy include pericarditis, progressive neuropathy attributable to uremia, encephalopathy, muscle irritability, anorexia and nausea that are not ameliorated by reasonable protein restriction, evidence of protein-energy malnutrition, and fluid and electrolyte abnormalities that are refractory to conservative measures. The latter include volume overload unresponsive to diuretic therapy, hyperkalemia unresponsive to dietary potassium restriction, and progressive metabolic acidosis that cannot be managed with alkali therapy. Clinical clues indicating the imminent development of uremic complications are a history of hiccupping, intractable pruritus, morning nausea and vomiting, muscle twitching and cramps, and the presence of asterixis on physical examination. In addition, the patient whose follow-up and compliance with conservative management are questionable should be considered for earlier initiation of renal replacement therapy, lest potentially life-threatening uremic complications or electrolyte disturbances supervene.

Since there is considerable interindividual variability in the severity of uremic symptoms and renal function, it is ill-advised to assign a certain "usual" level of blood urea nitrogen, serum creatinine, or GFR2 to the need to start dialysis. Nevertheless, in the United States, the Health Care Financing Administration has assigned levels of serum creatinine and creatinine clearance to qualify for reimbursement from Medicare for patients receiving dialysis. Serum creatinine must be =700 umol/L (=8.0 mg/dL) and the creatinine clearance must be =10 mL/min. Recent controlled studies have failed to show a survival advantage for early initiation of renal replacement therapy prior to onset of clinical indications.

Patient Education and Adjustment Social, psychological, and physical preparation for the transition to renal replacement therapy and choice of the optimal initial modality is best accomplished with a gradual approach involving a multidisciplinary team. While conservative measures are being carried out in patients with CRD1, it is important to prepare them with an intensive educational program, explaining the likelihood and timing of initiation of renal replacement therapy and the various forms of therapy available. The more knowledgable patients are concerning hemodialysis, peritoneal dialysis, and transplantation, the easier and more appropriate will be their decisions at a later time. Exploration of social service support resources is of great importance. In those who may perform home dialysis or undergo transplantation, early education of family members for selection and preparation as a home dialysis helper or a related donor for transplantation should occur long before the onset of symptomatic renal failure.

Selection of patients to be treated with various modalities of dialysis or transplantation is a matter of some debate, with considerable variation in different parts of the world. In general, in the United States and some other countries, nearly all patients who have reached ESRD36 are accepted for dialysis if they or their families desire prolongation of life, irrespective of age.

Only kidney transplantation (Chap. 263) offers the potential for nearly complete rehabilitation. This is because dialysis techniques replace only 10 to 15% of normal kidney function at the level of small-solute removal and are even less efficient at the removal of larger solutes. Generally, kidney transplantation follows a prior period of dialysis treatment. All patients in whom an acute reversible component of renal failure has not been completely excluded should be supported with dialysis first, at least for some period of time, to allow for possible return of renal function before consideration of transplantation. Recovery of endogenous renal function in patients treated with dialysis for 6 months is a rare occurrence. For patients approaching ESRD37 in whom a reversible component has been excluded, and who have a good antigenic match with a willing donor, consideration should be given to preemptive or primary transplantation without intervening dialysis.


	3. dialysis

Disclaimer: Not mine.. no money made.. don't sue me..

DIALYSIS IN THE TREATMENT OF RENAL FAILURE - Ajay K. Singh, Barry M. Brenner

INTRODUCTION

With the widespread availability of dialysis, the lives of hundreds of thousands of patients with end-stage renal disease (ESRD) have been prolonged. In the United States alone, there are now approximately 400,000 patients with ESRD. The overall incidence of ESRD is 260 cases per million population per year. The incident population of patients with ESRD is increasing at approximately 6% each year. The incidence of ESRD is disproportionately higher in African Americans (843 per million population per year) as compared with white Americans (189 per million population per year). In the United States, the leading cause of ESRD is diabetes mellitus, currently accounting for nearly 45% of newly diagnosed cases of ESRD. The second most common cause is hypertension, which is estimated to cause 28% of ESRD cases. Other causes of ESRD include glomerulonephritis, polycystic kidney disease, and obstructive uropathy. The mortality of patients with ESRD is lowest in Europe and Japan but is very high in the developing world because of the limited availability of dialysis. In the United States, the mortality rate of patients on dialysis is approximately 18% per year. Deaths are due mainly to cardiovascular diseases and infections (approximately 50% and 15% of deaths, respectively).

TREATMENT OPTIONS FOR ESRD1 PATIENTS

Commonly accepted criteria for placing patients on dialysis include the presence of the uremic syndrome; the presence of hyperkalemia unresponsive to conservative measures; extracellular volume expansion; acidosis refractory to medical therapy; a bleeding diathesis; and a creatinine clearance of 10 mL/min per 1.73 m2. Early referral to a nephrologist for advanced planning and creation of a dialysis access, education about ESRD1 treatment options, and the aggressive management of the complications of chronic renal failure, including acidosis, anemia, and hyperparathyroidism, are important. In addition to carefully evaluating patients for the onset of uremia (Chap. 261), regular measurement of renal function is important.

Renal function can be assessed indirectly by measurement of serum creatinine and blood urea nitrogen or of creatinine and urea clearance, or directly by measurement of glomerular filtration rate (GFR) using a radioisotope such as iothalamate. Creatinine clearance usually overestimates GFR because a substantial fraction of creatinine excretion in advanced renal failure occurs as a consequence of proximal tubular secretion. On the other hand, urea clearance invariably underestimates GFR because urea is reabsorbed in the distal nephron. Thus, when measurement of GFR by a direct test is not available, the average of the sum of the creatinine and urea clearance, or a cimetidine-blocked creatinine clearance (cimetidine blocks proximal tubular secretion), is recommended. Alternatively, the GFR can be estimated using a prediction equation that computes a calculated value for GFR. Examples of such equations include the Cockcroft-Gault equation and the Modification of Diet in Renal Disease (MDRD) equation.

The treatment options available for patients with renal failure depend on whether it is acute or chronic (Fig. 262-1). In acute renal failure, treatments include hemodialysis, continuous renal replacement therapies (Chap. 260), and peritoneal dialysis. In chronic renal failure (ESRD)1 the options include hemodialysis (in center or at home); peritoneal dialysis, as either continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD); or transplantation (Chap. 263). Although there are geographic variations, hemodialysis remains the most common therapeutic modality for ESRD (80% of patients in the United States). The choice between hemodialysis and peritoneal dialysis involves the interplay of various factors that include the patient's age, the presence of comorbid conditions, the ability to perform the procedure, and the patient's own conceptions about the therapy. Peritoneal dialysis is favored in younger patients because of their better manual dexterity and greater visual acuity, and because younger patients prefer the independence and flexibility of home-based peritoneal dialysis treatment. In contrast, larger patients (80 kg), patients with no residual renal function, and patients who have truncal obesity with or without prior abdominal surgery may be more suited to hemodialysis. Larger patients with no residual renal function are more appropriate for hemodialysis because these patients have a large volume of distribution of urea and require significantly higher amounts of peritoneal dialysis, which may be difficult to achieve because of the limited willingness of patients to perform more than four exchanges each day. In some patients, the inability to obtain vascular access necessitates a switch from hemodialysis to peritoneal dialysis.

HEMODIALYSIS

Hemodialysis relies on the principles of solute diffusion across a semipermeable membrane. Movement of metabolic waste products takes place down a concentration gradient from the circulation into the dialysate. The rate of diffusive transport increases in response to several factors, including the magnitude of the concentration gradient, the membrane surface area, and the mass transfer coefficient of the membrane. The latter is a function of the porosity and thickness of the membrane, the size of the solute molecule, and the conditions of flow on the two sides of the membrane. According to the laws of diffusion, the larger the molecule, the slower its rate of transfer across the membrane. A small molecule such as urea (60 Da) undergoes substantial clearance, whereas a larger molecule such as creatinine (113 Da) is cleared less efficiently. In addition to diffusive clearance, movement of toxic materials such as urea from the circulation into the dialysate may occur as a result of ultrafiltration. Convective clearance occurs because of solvent drag with solutes getting swept along with water across the semipermeable dialysis membrane.

THE DIALYZER

There are three essential components to dialysis: the dialyzer, the composition and delivery of the dialysate, and the blood delivery system (Fig. 262-2). The dialyzer consists of a plastic device with the facility to perfuse blood and dialysate compartments at very high flow rates. The surface area of dialysis membranes in adult patients is usually in the range of 0.8 to 1.2 m2.

There are currently two geometric configurations for dialyzers: hollow fiber and flat plate. The hollow fiber dialyzer is the most common in use in the United States. These dialyzers are composed of bundles of capillary tubes through which blood circulates while dialysate travels on the outside of the fiber bundle. In contrast, the less frequently utilized flat plate dialyzers are composed of sandwiched sheets of membrane in a parallel plate configuration. The advantage of the hollow fiber construction is the lower priming volume (60 to 90 mL vs 100 to 120 mL for the flat plate) and easier reprocessing of the filter for reuse in future dialysis treatments.

Recent advances have led to the development of many different types of membrane material. Broadly, there are four categories of dialysis membranes: cellulose, substituted cellulose, cellulosynthetic, and synthetic. Over the past two decades, there has been a gradual switch from cellulose-derived to synthetic membranes, because the latter are more biocompatible. Bioincompatibility may be defined as the ability of the membrane to activate the complement cascade. Cellulosic membranes are bioincompatible because of the presence of free hydroxyl groups on the membrane surface. In contrast, with the substituted cellulose membranes (e.g., cellulose acetate) or the cellulosynthetic membranes, the hydroxyl groups are chemically bonded to either acetate or tertiary amino groups, resulting in limited complement activation. Synthetic membranes, such as polysulfone, polymethylmethacrylate, and polyacrylonitrile membranes, are more biocompatible because of the absence of these hydroxyl groups. Polysulfone membranes are now used in over 60% of the dialysis treatments in the United States.

Reprocessing and reuse of hemodialyzers are employed for patients on chronic hemodialysis in nearly 80% of dialysis centers in the United States, in large part because of the expense of individual dialyzers. Evidence also suggests that reuse reduces complement activation, the incidence of anaphylactoid reactions to the membrane (first-use syndrome), and, in some studies, mortality rates among dialysis patients. In most centers, only the dialyzer unit is reprocessed and reused, whereas in the developing world blood lines are also frequently reused. The reprocessing procedure can be either manual or automated. It consists of the sequential rinsing of the blood and dialysate compartments with water, a chemical cleansing step with reverse ultrafiltration from the dialysate to the blood compartment, the testing of the patency of the dialyzer, and, finally, disinfection of the dialyzer. Formaldehyde, peracetic acid-hydrogen peroxide, and glutaraldehyde are the most frequently used reprocessing agents, with peracetic acid-hydrogen peroxide being the most common.

DIALYSATE

The composition of dialysate is listed in Table 262-1. Bicarbonate has replaced acetate as the preferred buffer in the United States. This change has resulted in fewer episodes of hypotension during dialysis. The potassium concentration of dialysate may be varied from 0 to 4 mmol/L depending on the predialysis plasma potassium concentration. The usual dialysate calcium concentration is 1.25 mmol/L (2.5 meq/L). The usual dialysate sodium concentration is 140 mmol/L. Lower dialysate sodium concentrations are associated with a higher frequency of hypotension, cramping, nausea, vomiting, fatigue, and dizziness. In patients who frequently develop hypotension during their dialysis run, sodium modeling to counterbalance urea-related osmolar gradients is now widely used. In this technique, the dialysate sodium concentration is gradually lowered from the range of 148 to 160 meq/L to isotonic levels (140 meq/L) near the end of the dialysis treatment. A dialysate glucose concentration of 200 mg/dL (11 mmol/L) is used to optimize blood glucose concentrations. Because patients are exposed to approximately 120 L of water during each dialysis treatment, untreated water could expose them to a variety of environmental contaminants. Therefore, in 98% of U.S. dialysis centers, water used for the dialysate is subjected to filtration, softening, deionization, and, ultimately, reverse osmosis. During the reverse osmosis process, water is forced through a semipermeable membrane at very high pressure to remove microbiologic contaminants and more than 90% of dissolved ions.

BLOOD DELIVERY SYSTEM

The blood delivery system is composed of the extracorporeal circuit in the dialysis machine and the dialysis access. The dialysis machine consists of a blood pump, dialysis solution delivery system, and various safety monitors. The blood pump, using a roller mechanism, moves blood from the access site, through the dialyzer, and back to the patient. The blood flow rate may range from 250 to 500 mL/min. Negative hydrostatic pressure on the dialysate side can be manipulated to achieve desirable fluid removal: so-called ultrafiltration. Dialysis membranes have different ultrafiltration coefficients (i.e., mL removed/min per mmHg) so that along with hydrostatic changes, fluid removal can be varied. The dialysis solution delivery system dilutes the dialysate concentrate with water and monitors the temperature, conductivity, and flow of dialysate. The dialysate may be delivered to the dialyzer from a storage tank or a proportioning system that manufactures dialysate online.

Dialysis Access The fistula, graft, or catheter through which blood is obtained for hemodialysis is often referred to as a dialysis access. A native fistula created by the anastomosis of an artery to a vein (e.g., the Cimino-Breschia fistula, in which the cephalic vein is anastomosed to the radial artery) results in arterialization of the vein. This facilitates its subsequent use in the placement of large needles (typically 15 gauge) to access the circulation. Although fistulas have a high patency rate (approximately 60% are patent at 3 years following creation), fistulas are created in only approximately 30% of patients in the United States. In the majority of U.S. dialysis patients, the dialysis access consists of an arteriovenous graft that interposes prosthetic material, such as polytetrafluoroethylene, between an artery and a vein. Reasons for the higher rates of graft placement include the late referral of patients to vascular access surgeons so that by the time surgery is planned, the patient's arm veins have already been obliterated through multiple blood draws; the high prevalence of patients with diabetes mellitus and its associated microvascular disease; and the greater surgical skill required in creating a fistula. However, by 3 years most grafts fail because of thrombosis or infection. Fortunately, grafts may be inserted in one of several locations: the arm (brachial artery to basilic vein), the chest wall (axillary artery to axillary vein), or the leg (femoral artery to femoral vein). The most common access-related complication is thrombosis due to intimal hyperplasia, which results in stenosis 2 to 3 cm proximal to the venous anastomosis.

A double-lumen cuffed catheter is used in approximately 20% of patients on chronic hemodialysis in the United States. These catheters are used as an alternative to either a native arteriovenous fistula or a graft in selected patients in whom dialysis is required relatively urgently, such as patients who manifest delayed recovery from acute renal failure, or where a further permanent access procedure (e.g., arteriovenous fistula or arteriovenous graft) is not feasible for anatomical reasons. Although double-lumen catheters may permit blood flows comparable to a permanent arteriovenous access, these catheters are prone to infection and to occlusion because of thrombosis. Temporary double-lumen catheters in either the femoral vein or the internal jugular or subclavian vein are usually employed in patients with acute renal failure. The jugular is preferred to the subclavian vein because, for unclear reasons, a catheter placed in a subclavian vein appears to be associated with a higher rate of venous stenosis. Temporary access can be used for 2 to 3 weeks. Thrombosis, low blood flow, and infection limit the life of the catheter.

GOALS OF DIALYSIS

The hemodialysis procedure is targeted at removing both low- and high-molecular-weight solutes. The procedure consists of pumping heparinized blood through the dialyzer at a flow rate of 300 to 500 mL/min, while dialysate flows in an opposite counter-current direction at 500 to 800 mL/min. The clearance of urea ranges from 200 to 350 mL/min, while the clearance of a2 microglobulin is more modest and ranges from 20 to 25 mL/min. The efficiency of dialysis is determined by blood and dialysate flow through the dialyzer, as well as dialyzer characteristics (i.e., its efficiency in removing solute). The dose of dialysis, which is defined as the magnitude of urea clearance during a single dialysis treatment, is further governed by patient size, residual renal function, dietary protein intake, the degree of anabolism or catabolism, and the presence of comorbid conditions.

Since the landmark studies of Sargent and Gatch relating the measurement of the dose of dialysis using urea concentration with patient outcome, the delivered dose of dialysis has been correlated with morbidity and mortality. This has led to the development of two major models for assessing the adequacy of the dialysis dose. Fundamentally, these two widely used measures of the adequacy of dialysis are calculated from the decrease in the blood urea nitrogen concentration during the dialysis treatment — that is, the urea reduction ratio (URR), and KT/V, an index based on the urea clearance rate, K, and the size of the urea pool, represented as the urea distribution volume, V. K, which is the sum of clearance by the dialyzer plus renal clearance, is multiplied by the time spent on dialysis, T. Increasingly, KT/V has become the preferred marker for dialysis adequacy. Currently, a URR of 65% and a KT/V of 1.2 per treatment are minimal standards for adequacy among ESRD1 patients; lower levels of dialysis treatment are associated with increased morbidity and mortality. The HEMO study examined the effect of dialysis dose and the level of flux of the dialyzer membrane on mortality and morbidity and found that a higher dialysis dose (single pool KT/V of 1.71 ± 0.11) did not confer a benefit over a standard dialysis dose (single pool KT/V of 1.32 ± 0.09). Thus, the study supported the continued use of current US Practice Guidelines, which recommend a KT/V of at least 1.2. Furthermore, since no benefit of a high flux dialyzer was demonstrated in the study, the use of a high flux dialyzer was also not supported.

For the majority of patients with chronic renal failure, between 9 and 12 h of dialysis is required each week, usually divided into three equal sessions. However, the dialysis dose must be individualized. Recently there has been much interest in the possibility that more frequent dialysis may be associated with improved outcomes in patients with acute or chronic renal failure. Indeed, it has been suggested that among patients with acute renal failure, daily dialysis may better control uremia, reduce hypotensive episodes, more rapidly resolve acute renal failure, and significantly lower mortality. Therefore, the measurement of dialysis adequacy using KT/V or the URR2 should serve only as a guide; body size, residual renal function, dietary intake, complicating illness, degree of anabolism or catabolism, and the presence of large interdialytic fluid gains should be important factors that are taken into consideration in the dialysis prescription.

COMPLICATIONS DURING HEMODIALYSIS

Hypotension is the most common acute complication of hemodialysis, particularly among diabetics. Numerous factors appear to increase the risk of hypotension, including excessive ultrafiltration with inadequate compensatory vascular filling, impaired vasoactive or autonomic responses, osmolar shifts, food ingestion, impaired cardiac reserve, diastolic dysfunction, the use of antihypertensive drugs, anemia, and vasodilation due to the use of warm dialysate. Because of the vasodilatory and cardiodepressive effects of acetate, the use of acetate as the buffer in dialysate was once a common cause of hypotension. Since the introduction of bicarbonate-containing dialysate, dialysis-associated hypotension has become less common. The management of hypotension during dialysis consists of discontinuing ultrafiltration, the administration of 100 to 250 mL of isotonic saline or 10 mL of 23% saturated hypertonic saline, and administration of salt-poor albumin. Hypotension during dialysis can frequently be prevented by careful evaluation of the dry weight, withholding of antihypertensive medications on the day prior to and on the day of dialysis, and avoiding heavy meals during dialysis. Additional maneuvers include ultrafiltration modeling, such that more fluid is ultrafiltered at the beginning rather than the end of the dialysis procedure; the performance of sequential ultrafiltration followed by dialysis; the use of midodrine, a selective a1-adrenergic pressor agent; and cooling of the dialysate during dialysis treatment.

Muscle cramps during dialysis are also a common complication of the procedure. However, since the introduction of volumetric controls on dialysis machines and sodium modeling, the incidence of cramps has fallen. The etiology of dialysis-associated cramps remains obscure. Changes in muscle perfusion because of excessively aggressive volume removal, particularly below the estimated dry weight, and the use of low-sodium-containing dialysate, have been proposed as precipitants of dialysis-associated cramps. Strategies that may be used to prevent cramps include reducing volume removal during dialysis, the use of higher concentrations of sodium in the dialysate, and the use of quinine sulfate (260 mg 2 h before treatment).

Anaphylactoid reactions to the dialyzer, particularly on its first use, have been reported most frequently with the bioincompatible cellulosic-containing membranes. With the gradual phasing out of cuprophane membranes in the United States, the first-use syndrome has become relatively uncommon. The first-use syndrome consists of either an intermediate hypersensitivity reaction due to an IgE-mediated reaction to ethylene oxide used in the sterilization of new dialyzers, or a symptom complex of nonspecific chest and back pain, which appears to result from complement activation and cytokine release.

The major cause of death in patients with ESRD1 receiving chronic dialysis is cardiovascular disease. The rate of death from cardiac disease is higher in patients on hemodialysis as compared to patients on peritoneal dialysis and renal transplantation. The underlying cause of cardiovascular disease is unclear but may be related to the inadequate treatment of hypertension; the presence of hyperlipidemia, homocystinemia and anemia; the calcification of coronary arteries in patients with an elevated calcium-phosphorus product; and perhaps alterations in cardiovascular dynamics during the dialysis treatment. Intensive investigation of the mechanisms and potential interventions that could impact on reducing the mortality from cardiovascular causes is currently underway.

CONTINUOUS RENAL REPLACEMENT THERAPY

Continuous renal replacement therapies (CRRT) have become increasingly prevalent in the intensive care unit (ICU) setting for management of acute renal failure. The advantages of CRRT over intermittent hemodialysis are that it is usually better tolerated hemodynamically; it facilitates gradual correction of biochemical abnormalities; it is highly effective in removing fluid; and it is technically simple to perform. Clearance of toxic materials (using urea as the marker) can occur with CRRT from convective clearance alone if the ultrafiltration rate is high and with diffusive clearance if dialysis accompanies ultrafiltration. CRRT techniques include continuous arteriovenous hemodiafiltration (CAVH/D) with or without dialysis, and continuous veno-venous hemodiafiltration (CVVH/D) with or without dialysis.

Veno-venous therapies differ fundamentally from arteriovenous therapies in that veno-venous therapies do not require arterial access. This allows obtaining less risky and easier vascular access. However, because there is no systemic arterial pressure to drive hemofiltration, veno-venous therapies require a blood pump in the extracorporeal circuit. Veno-venous therapies such as CVVH provide substantial flexibility because changing the blood flow rate in the pump can change the ultrafiltration and clearance rates. In contrast, arteriovenous therapies such as CAVH are associated with variable efficiency because the systemic blood pressure is frequently low or unstable in patients with acute renal failure. Furthermore, low blood flow with CAVH may also result in clotting of the extracorporeal circuit. CAVH often results in clearance rates as low as 10 to 15 mL/min, whereas CVVH may generate clearances in the range of 30 to 40 mL/min. Thus, in light of these advantages of CVVH, many centers have completely switched from arteriovenous to veno-venous therapies in patients with acute renal failure in the ICU setting.

Vascular access in patients on CVVH3 is usually achieved by the insertion of a double-lumen catheter into the femoral vein. The blood pump is typically set to deliver approximately 150 to 180 mL/min. In automated systems, (e.g., the Cobe Prisma system), the treatment is volumetrically governed by continuously weighing the effluent and replacement solutions and using a servomechanism to drive the replacement fluid pump at a rate computed either to balance the inflow and loss of fluid or to maintain a predetermined rate of fluid loss. Anticoagulation of the extracorporeal circuit is via a heparin infusion (200 to 1600 U/h) through the inflow side of the circuit. Alternatively, citrate can be used to chelate calcium in the extracorporeal circuit to provide regional anticoagulation in selected patients who cannot undergo systemic heparinization. The replacement solution in continuous therapies is designed specifically to replace calcium, magnesium, and bicarbonate. In place of bicarbonate, lactate or citrate is the buffer in the replacement solution. However, bicarbonate-based replacement fluid is the preferred option in patients with liver failure because of the impaired ability of the liver to metabolize either lactate or acetate into bicarbonate.

PERITONEAL DIALYSIS

Peritoneal dialysis consists of infusing 1 to 3 L of a dextrose-containing solution into the peritoneal cavity and allowing the fluid to dwell for 2 to 4 h. As with hemodialysis, toxic materials are removed through a combination of convective clearance generated through ultrafiltration, and diffusive clearance down a concentration gradient. The clearance of solute and water during a peritoneal dialysis exchange depends on the balance between the movement of solute and water into the peritoneal cavity versus absorption from the peritoneal cavity. The rate of diffusion diminishes with time and eventually stops when equilibration between plasma and dialysate is reached. Absorption of solutes and water from the peritoneal cavity occurs across the peritoneal membrane into the peritoneal capillary circulation and via peritoneal lymphatics into the lymphatic circulation. The rate of peritoneal solute transport varies from patient to patient and may be altered by the presence of infection (peritonitis), drugs such as beta blockers and calcium channel blockers, and physical factors such as position and exercise.

FORMS OF PERITONEAL DIALYSIS

Peritoneal dialysis may be carried out as continuous ambulatory peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), or nocturnal intermittent peritoneal dialysis (NIPD). In CAPD, dialysis solution is manually infused into the peritoneal cavity during the day and exchanged three to four times daily. A nighttime dwell is frequently instilled at bedtime and remains in the peritoneal cavity through the night. The drainage of spent dialysate (effluence) is performed manually with the assistance of gravity to move fluid out of the abdomen. In CCPD, exchanges are performed in an automated fashion, usually at night; the patient is connected to the automated cycler, which then performs four to five exchange cycles while the patient sleeps. Peritoneal dialysis cyclers automatically cycle dialysate in and out of the abdominal cavity. In the morning the patient, with the last exchange remaining in the abdomen, is disconnected from the cycler and goes about his regular daily activities. In NIPD, the patient is given approximately 10 h of cycling each night, with the abdomen left dry during the day.

Peritoneal dialysis solutions are available in various volumes ranging from 0.5 to 3.0 L. The electrolyte composition is shown in Table 262-2. Lactate is the preferred buffer in peritoneal dialysis solutions. Acetate in peritoneal dialysis solutions appears to accelerate peritoneal sclerosis, whereas use of bicarbonate results in precipitation of calcium and caramelization of glucose. The most common additives to peritoneal dialysis solutions are heparin and antibiotics during an episode of acute peritonitis. Insulin may also be added in patients with diabetes mellitus.

ACCESS TO THE PERITONEAL CAVITY

This is obtained through a peritoneal catheter. These are either acute catheters, used to perform acute continuous peritoneal dialysis, usually in an emergency setting, or chronic catheters, which have either one or two Dacron cuffs and are tunneled under the skin into the peritoneal cavity. An acute catheter consists of a straight or slightly curved rigid tube with several holes at its distal end. Catheters can be inserted at the bedside by making a small incision in the anterior abdominal wall; the catheter is inserted with the assistance of a guidewire or stylet. Acute catheters are anchored externally with adhesives or sutures and are usually reserved for temporary use because of the risk of infection, which increases after 72 h of use. In contrast, chronic catheters are flexible and made of silicon rubber with numerous side holes at the distal end. These chronic catheters usually have two Dacron cuffs to promote fibroblast proliferation, granulation, and invasion of the cuff. The scarring that occurs around the cuffs anchors the catheter and seals it from bacteria tracking from the skin surface into the peritoneal cavity; it also prevents the external leakage of fluid from the peritoneal cavity. The cuffs are placed in the preperitoneal plane and approximately 2 cm from the skin surface. The most common chronic peritoneal dialysis catheter in use is the Tenckhoff catheter, which contains two cuffs.

The initial CAPD4 prescription consists of the infusion of a 2-L volume of a 1.5% dextrose concentration peritoneal dialysis solution into the peritoneal cavity over 10 min and allowing it to dwell for 2.5 h. The effluent solution is then drained over 20 min before the next exchange. Three daytime exchanges are accompanied by a 2-L nighttime dwell as the standard prescription. Because peritoneal membrane characteristics vary from one individual to another, the peritoneal equilibrium test should be employed within 2 months of a patient initiating peritoneal dialysis. This test measures the peritoneal membrane transfer rate for solutes (usually urea and creatinine) based on the ratio of their concentration in dialysate and plasma at specific times during the dialysate dwell. It allows patients to be classified as low, low-average, high-average, and high transporters. Approximately 10 to 17% of patients are high transporters, 50% high-average transporters, 25 to 30% low-average transporters, and 1 to 5% low transporters. Identifying the high transporters early is important, since these patients not only demonstrate excellent solute removal, they also absorb glucose rapidly; maximum ultrafiltration occurs early in the dwell, followed by reabsorption of water back into the circulation over the course of the dwell. Such patients benefit from either NIPD5 or CAPD without a nighttime dwell.

The dose of peritoneal dialysis required to provide adequate or optimal dialysis as measured by patient outcomes is not known. However, there is emerging consensus that the weekly KT/V should be 2.0 and the creatinine clearance 65 L/week per 1.73 m2. The most frequently utilized approach to calculating a weekly KT/V and creatinine clearance is to collect the spent dialysate and urine over a 24-h period. The peritoneal dialysis prescription can be tailored to improve suboptimal clearance values by increasing the volume of individual exchanges, increasing the number of exchanges, or combining the CAPD6 and CCPD7 techniques. In combining these techniques, the CAPD patient hooks up to a cycler at night and the machine automatically performs one or two nocturnal exchanges, whereas the CCPD patient makes an additional manual daytime exchange.


	4. transplant

Disclaimer: Not mine.. no money made.. don't sue me..

TRANSPLANTATION IN THE TREATMENT OF RENAL FAILURE - Charles B. Carpenter, Edgar L. Milford, Mohamed H. Sayegh

INTRODUCTION

Transplantation of the human kidney is frequently the most effective treatment of advanced chronic renal failure. Worldwide, tens of thousands of such procedures have been performed. When azathioprine and prednisone were initially used as immunosuppressive drugs in the 1960s, the results with properly matched familial donors were superior to those with organs from cadaveric donors, namely, 75 to 90% compared with 50 to 60% graft survival rates at 1 year. During the 1970s and 1980s, the success rate at the 1-year mark for cadaveric transplants rose progressively. By the time cyclosporine was introduced in the early 1980s, cadaveric donor grafts had a 70% 1-year survival and reached the 82% level in the mid-1990s and 88% by 1998 (Fig. 263-1). After the first year, graft survival curves show an exponential decline in numbers of functioning grafts from which a half-life (t1/2) in years is calculated; this has increased by 2 years since the 1980s (Fig. 263-1).

Mortality rates after transplantation are highest in the first year and are age-related: 2% for ages 18 to 34 years, 3% for ages 35 to 49 years, and 6.8% for ages over 50 to 60 years. These rates compare favorably to those in the chronic dialysis population, even after risk adjustments for age, diabetes, and cardiovascular status. Occasionally, acute irreversible rejection may occur after many months of good function, especially if the patient neglects to take the immunosuppressive drugs. Most grafts, however, succumb at varying rates to a chronic vascular and interstitial obliterative process termed chronic rejection, although its pathogenesis is incompletely understood. Overall, transplantation returns the majority of patients to an improved lifestyle and an improved life expectancy, as compared to patients on dialysis; however, careful prospective cohort studies have yet to be reported.

RECIPIENT SELECTION

There are few absolute contraindications to renal transplantation. The transplant procedure is relatively noninvasive, as the organ is placed in the inguinal fossa without entering the peritoneal cavity. Recipients without perioperative complications can often be discharged from the hospital in excellent condition within 5 days of the operation.

Virtually all end-stage renal disease (ESRD) patients who receive a transplant have a higher life expectancy than risk-matched patients who remain on dialysis. Even though diabetics or older candidates have a higher mortality rate than other transplant recipients, their survival is improved with transplantation compared to remaining on dialysis. This global benefit of transplantation as a treatment modality poses substantial ethical issues for policy makers, as the number of cadaveric kidneys available is far from sufficient to meet the current needs of the candidates. Waiting lists continue to grow, and the average wait time for a cadaver kidney is now 4 years in many locales. The current standard of care is that the candidate should have a life expectancy of 5 years to be put on a cadaver organ wait list. Even for living donation, the candidate should have 5 years of life expectancy. This is because the benefits of kidney transplantation over dialysis are only realized after a perioperative period in which the mortality is higher in transplanted patients than in dialysis patients with comparable risk profile.

All candidates must have a thorough risk/benefit evaluation prior to being approved for transplantation. In particular, an aggressive approach to diagnosis of correctable coronary artery disease, presence of latent or indolent infection (HIV, hepatitis B or C, tuberculosis), and neoplasm should be a routine part of the candidate workup. Most transplant centers consider overt AIDS and active hepatitis to be an absolute contraindication to transplantation because of the high risk of opportunistic infection. Some centers are now transplanting individuals with hepatitis and even HIV infection under strict protocols to determine whether the risks and benefits favor transplantation over dialysis.

Among the few absolute contraindications to transplantation is the presence of potentially harmful antibody against the donor kidney at the time of the anticipated transplant. Harmful antibodies that can cause very early graft loss include natural antibodies against the ABO blood group antigens and antibodies against HLA-class I (A, B, C) or class II (DR) antigens. These antibodies are routinely excluded by proper pretransplant screening of the candidates, ABO and HLA typing of donor and recipient, and cross-matching of candidate serum with that of the donor.

DONOR SELECTION

Donors can be cadavers or volunteer living donors. The latter are usually family members selected to have at least partial compatibility for HLA antigens. Living volunteer donors should be normal on physical examination and of the same major ABO blood group, because crossing major blood group barriers prejudices survival of the allograft. It is possible, however, to transplant a kidney of a type O donor into an A, B, or AB recipient. Selective renal arteriography should be performed on donors to rule out the presence of multiple or abnormal renal arteries, because the surgical procedure is difficult and the ischemic time of the transplanted kidney long when vascular abnormalities exist. Transplant surgeons are now using a laparascopic method to isolate and remove the living donor kidney. This operation has the advantage of less evident surgical scars, and, because there is less tissue trauma, the laparoscopic donors have a substantially shorter hospital stay and less discomfort than those who have the traditional surgery. Cadaveric donors should be free of malignant neoplastic disease, hepatitis, and HIV1 because of possible transmission to the recipient. Increased risk of graft failure exists when the donor is elderly or has renal failure and when the kidney has a prolonged period of ischemia and storage.

In the United States, there is a coordinated national system of regulations, allocation support, and outcomes analysis for kidney transplantation called the Organ Procurement Transplant Network. It is now possible to remove cadaver kidneys and to maintain them for up to 48 h on cold pulsatile perfusion or simple flushing and cooling. This permits adequate time for typing, cross-matching, transportation, and selection problems to be solved.

TISSUE TYPING AND CLINICAL IMMUNOGENETICS

Matching for antigens of the HLA major histocompatibility gene complex (Chap. 296) is an important criterion for selection of donors for renal allografts. Each mammalian species has a single chromosomal region that encodes the strong, or major, transplantation antigens, and this region on the human sixth chromosome is called HLA. HLA antigens have been classically defined by serologic techniques, but methods to define specific nucleotide sequences in genomic DNA are increasingly being used. Other antigens, called "minor," may nevertheless play crucial roles, in addition to the ABH(O) blood groups and endothelial antigens that are not shared with lymphocytes. The Rh system is not expressed on graft tissue. Evidence for designation of HLA as the genetic region encoding major transplantation antigens comes from the success rate in living related donor renal and bone marrow transplantation, with superior results in HLA-identical sibling pairs. Nevertheless, 5% of HLA-identical renal allografts are rejected, often within the first weeks after transplantation. These failures represent states of prior sensitization to non-HLA antigens. Non-HLA minor antigens are relatively weak when initially encountered and are therefore suppressible by conventional immunosuppressive therapy. Once priming has occurred, however, secondary responses are much more refractory to treatment. ABO incompatibilities are hazardous because of the presence of natural anti-A and anti-B antibodies in recipients and the normal expression of A and B blood group substances on endothelium, resulting in immediate vascular injury.

Living Donors When first-degree relatives are donors, graft survival rates at 1 year are 5 to 7% greater than those for cadaver grafts. The 5-year survival rates still favor the partially matched (3/6 HLA mismatched) family donor over a randomly selected cadaver donor (Table 263-1). In addition, living donors provide the advantage of immediate availability. For both living and cadaveric donors, the 5-year outcomes are poor if there is a complete (6/6) HLA mismatch. Waiting lists for cadaveric kidneys have grown faster than the available organ supply, to the point where most new patients with ESRD2 wait for 4 years. In response to this increasing disparity between cadaver donor supply and patient demand, living unrelated volunteers, usually spouses or close friends, are being accepted as donors in increasing numbers. The survival rate of living unrelated renal allografts is as good or better than that of perfectly HLA matched cadaver renal transplants and comparable to that of kidneys from living relatives. This is likely to be a consequence both of short cold ischemia time and the extra care taken to document that the condition and renal function of the donor are optimal before proceeding with a living unrelated donation (Table 263-1). It is illegal in the United States to purchase organs for transplantation.

Concern has been expressed regarding the potential risk to a volunteer kidney donor of premature renal failure after several years of increased blood flow and hyperfiltration per nephron in the remaining kidney. There are a few reports of the development of hypertension, proteinuria, and even lesions of focal segmental sclerosis in donors under long-term follow-up. Difficulties in donors followed for =20 years are unusual, however, and it may be that having a single kidney becomes significant only when another condition, such as hypertension, is superimposed. It is also desirable to consider the risk of development of type 1 diabetes mellitus in a family member who is a potential donor to a diabetic renal failure patient. Anti-insulin and anti-islet antibodies should be measured, and glucose tolerance tests should be performed in such donors to rule out a prediabetic state.

HLA Matching and Cadaveric Donors The question of whether matching of HLA antigens in unrelated donor-recipient pairs would approximate the high initial success rates and slow rates of subsequent graft loss with HLA-identical sib pairs could not be answered until the late 1980s when reliable class II histocompatibility (DR) typing became widely available. Now that pooled data on tens of thousands of cadaveric renal transplants from all over the world are available, the HLA-matching effect can be clearly seen, especially in the long-term survival figures. It is shown in Table 263-1 that there is an overall beneficial effect of HLA matching in cadaveric grafts. With increasing numbers of mismatches for cadaveric donors, the 5-year survival drops from 68.2% to 55.3%. The survival rates at the 10-year mark are projected to range from 65 (zero mismatches) to 34% (six mismatches). There is controversy regarding the value of cadaveric organ-sharing rules that are based entirely upon the numbers of HLA mismatches. Giving preference to HLA zero-mismatched candidates (Table 263-1) is a top priority in the United States, however, and 20% of kidneys are transplanted on this basis. Table 263-1 also shows the interaction of HLA matching and graft ischemia on results; namely, kidneys from HLA-incompatible unrelated or spousal donors do better than those from similarly mismatched cadaver donors, suggesting that the additional ischemic injury of organ storage is important. Nevertheless, when such a cadaveric donor is HLA-compatible, the benefit of matching can still be seen.

Presensitization A positive cross match of recipient serum with donor T lymphocytes representing anti-HLA class I is usually predictive of an acute vasculitic event termed hyperacute rejection. Patients with anti-HLA antibodies can be safely transplanted if careful cross-matching of donor blood lymphocytes with recipient serum is performed. Patients sustained by dialysis often show fluctuating antibody titers and specificity patterns. At the time of assignment of a cadaveric kidney, cross matches are performed with at least a current serum. Previously analyzed antibody specificities and additional cross matches are performed accordingly. Techniques for cross-matching are not universally standardized; however, at least two techniques are employed in most laboratories. The minimal purpose for the cross match is avoidance of hyperacute rejection mediated by recipient antibodies to donor HLA class I antigens. Sensitive tests, such as the use of flow cytometry, can be useful for avoidance of accelerated, and often untreatable, early graft rejection in patients receiving second or third transplants. Donor T lymphocytes, which express only class I antigens, are used as targets for detection of anti-class I (HLA-A and -B) antibodies. Preformed anti-class II (HLA-DR) antibodies against the donor carry a higher risk of graft loss as well, particularly in recipients who have suffered early loss of a prior kidney transplant. B lymphocytes expressing both class I and class II antigens are used in these assays. Non-HLA antigens restricted in expression to endothelium and sometimes monocytes have been described, but clinical relevance is not well established. A series of minor histocompatibility antigens do not elicit antibodies, and sensitization to these is detectable only by cytotoxic T cells, an assay too cumbersome for routine use.

Blood Transfusions Exposure to leukocyte HLA antigens during transfusions is a major cause of sensitization that limits transplantation access and increases the risk of early graft rejection. In the 1970s, attempts to avoid all blood exposure in dialysed patients paradoxically increased the risk of graft rejection. The beneficial "transfusion effect" was never fully explained, and it almost disappeared in the 1980s as overall management of patients improved with the use of cyclosporine and more effective means of rejection treatment. Currently, with the use of erythropoietin the need for transfusion is much reduced. It has been noted, however, that nontransfused patients do have more rejection activity.

IMMUNOLOGY OF REJECTION

Both cellular and humoral (antibody-mediated) effector mechanisms can play roles in kidney transplant rejection. Antibodies directed against ABO blood group antigens and HLA class I or class II antigens can cause hyperacute rejection within minutes to hours of engraftment if they are present in the recipient at the time of engraftment. Such antibodies bind to vascular endothelium, cause activation of the complement cascade, and direct endothelial damage, platelet aggregation, microvascular thrombi, and in the most severe cases ischemic necrosis of the organ. Antibodies against ABO are naturally found in humans. Anti-HLA antibodies are produced as a consequence of prior blood transfusions, multiple pregnancies, or rejection of a prior HLA-incompatible transplant. Antibodies that bind to cells within the transplant can also initiate a form of antibody-dependent cell death mediated by recipient cells that bear receptors for the Fc portion of immunoglobulin.

Cellular rejection is mediated by lymphocytes that respond to HLA antigens expressed within the organ. The CD4+ lymphocyte responds to class II (HLA-DR) incompatibility by proliferating and releasing proinflammatory cytokines that augment the proliferative response of both CD4+ and CD8+ cells. CD8+ cytotoxic lymphocyte precursors respond primarily to class I (HLA-A, -B) antigens and mature into cytotoxic effector cells. The cytotoxic effector, or "killer" T, cells cause organ damage through direct contact and lysis of donor target cells. The natural role of HLA antigens is to present processed peptide fragments of antigen to T lymphocytes, the fragments residing in a "groove" of the HLA molecule distal to the cell surface. T cells can be directly stimulated by non-self HLA antigen expressed on donor parenchymal cells and residual donor leukocytes residing in the kidney interstitium. In addition, donor HLA molecules can be processed by a variety of donor or recipient cells capable of antigen presentation and then presented to T cells in the same manner as most other antigens. The former mode of stimulation is sometimes called direct presentation and the latter mode called indirect presentation (Fig. 263-2). There is evidence that non-HLA antigens can also play a role in renal transplant rejection episodes. Recipients who receive a kidney from an HLA-identical sibling can have rejection episodes and require maintenance immunosuppression, while identical twin transplants require no immunosuppression. There are documented non-HLA antigens, such as an endothelial-specific antigen system with limited polymorphism and a tubular antigen, which can be targets of humoral or cellular rejection responses, respectively.

IMMUNOSUPPRESSIVE TREATMENT

Immunosuppressive therapy, as presently available, generally suppresses all immune responses, including those to bacteria, fungi, and even malignant tumors. In the 1950s when clinical renal transplantation began, sublethal total-body irradiation was employed. We have now reached the point where sophisticated pharmacologic immunosuppression is available, but it still has the hazard of promoting infection and malignancy. In general, all clinically useful drugs are more selective to primary than to memory immune responses. Agents to suppress the immune response are discussed in the following paragraphs, and those currently in clinical use are listed in Table 263-2.

Drugs Azathioprine, an analogue of mercaptopurine, was for two decades the keystone to immunosuppressive therapy in humans. This agent can inhibit synthesis of DNA, RNA, or both. Because cell division and proliferation are a necessary part of the immune response to antigenic stimulation, suppression by this agent may be mediated by the inhibition of mitosis of immunologically competent lymphoid cells, interfering with synthesis of DNA. Alternatively, immunosuppression may be brought about by blocking the synthesis of RNA (possibly messenger RNA), inhibiting processing of antigens prior to lymphocyte stimulation. Therapy with azathioprine in doses of 1.5 to 2.0 mg/kg per day is generally added to cyclosporine as a means of decreasing the requirements for the latter. Because azathioprine is rapidly metabolized by the liver, its dosage need not be varied directly in relation to renal function, even though renal failure results in retention of the metabolites of azathioprine. Reduction in dosage is required because of leukopenia and occasionally thrombocytopenia. Excessive amounts of azathioprine may also cause jaundice, anemia, and alopecia. If it is essential to administer allopurinol concurrently, the azathioprine dose must be reduced, since inhibition of xanthine oxidase delays degradation. This combination is best avoided.

Mycophenolate mofetil is now used in place of azathioprine in many centers. It has a similar mode of action and a mild degree of gastrointestinal toxicity but produces minimal bone marrow suppression. Its advantage is its increased potency in preventing or reversing rejection. Patients with hyperuricemia can be given allopurinol without adjustment of the mycophenylate dose.

Glucocorticoids are important adjuncts to immunosuppressive therapy. Of all the agents employed, prednisone has effects that are easiest to assess, and in large doses it is usually effective for the reversal of rejection. In general, 200 to 300 mg prednisone is given immediately prior to or at the time of transplantation, and the dosage is reduced to 30 mg within a week. The side effects of the glucocorticoids, particularly impairment of wound healing and predisposition to infection, make it desirable to taper the dose as rapidly as possible in the immediate postoperative period. Customarily, methylprednisolone, 0.5 to 1.0 g intravenously, is administered immediately upon diagnosis of beginning rejection and continued once daily for 3 days. When the drug is effective, the results are usually apparent within 96 h. Such "pulse" doses are not effective in chronic rejection. Most patients whose renal function is stable after 6 months or a year do not require large doses of prednisone; maintenance doses of 10 to 15 mg/d are the rule. Many patients tolerate an alternate-day course of steroids without an increased risk of rejection.

A major effect of steroids is on the monocyte-macrophage system, preventing the release of interleukin (IL) 6 and IL-1. Lymphopenia after large doses of glucocorticoids is primarily due to sequestration of recirculating blood lymphocytes to lymphoid tissue.

Cyclosporine is a fungal peptide with potent immunosuppressive activity. It acts on the calcineurin pathway to block transcription of mRNA for IL3-2 and other proinflammatory cytokines, thereby inhibiting T cell proliferation. Although it works alone, cyclosporine is more effective in conjunction with glucocorticoids. Since cyclosporine blocks production of IL-2 by T cells, its combination with steroids is expected to produce a double block in the macrophage ? IL-6/IL-1 ? T cell ? IL-2 sequence. Clinical results with tens of thousands of renal transplants have been impressive. Of its toxic effects (nephrotoxicity, hepatotoxicity, hirsutism, tremor, gingival hyperplasia, diabetes), only nephrotoxicity presents a serious management problem and is further discussed below.

Tacrolimus (FK-506) is a fungal macrolide that has the same mode of action, and a similar side effect profile, as cyclosporine. It does not produce hirsutism or gingival hyperplasia, however. De novo induction of diabetes mellitus is more common with tacrolimus. The drug was first used in liver transplantation and may substitute for cyclosporine entirely or be tried as an alternative in renal patients whose rejections are poorly controlled by cyclosporine.

Sirolimus (previously called rapamycin) is another fungal macrolide but has a different mode of action, i.e., it inhibits T cell growth factor pathways, preventing the response to IL3-2 and other cytokines. Sirolimus can be used in conjunction with cyclosporine or tacrolimus as an alternative immunosuppressive regimen. Its use with tacrolimus alone shows promise as a steroid-sparing regimen, especially in patients who would benefit from pancreatic islet transplantation, where steroids have an adverse effect on islet survival.

Antibodies to Lymphocytes When serum from animals made immune to host lymphocytes is injected into the recipient, a marked suppression of cellular immunity to the tissue graft results. The action on cell-mediated immunity is greater than on humoral immunity. A globulin fraction of serum [antilymphocyte globulin (ALG)] is the agent generally employed. For use in humans, peripheral human lymphocytes, thymocytes, or lymphocytes from spleens or thoracic duct fistulas have been injected into horses, rabbits, or goats to produce antilymphocyte serum, from which the globulin fraction is then separated. Monoclonal antibodies against defined lymphocyte subsets offer a more precise and standardized form of therapy. OKT3 is directed to the CD3 molecules that form a portion of the T cell antigen-receptor complex; hence CD3 is expressed on all mature T cells. CD4 or CD8 molecules also form part of the fully activated cluster of molecules, and monoclonal antibodies to these offer the potential for more selective targeting of T cell subsets.

Another approach to more selective therapy is to target the 55-kDa alpha chain of the IL3-2 receptor, expressed only on T cells that have been recently activated. The problem with such mouse antibodies is the potential for developing human antimouse antibodies (HAMA), an event that limits the effective period of use. Genetically engineered monoclonal antibodies can solve this problem. Two such antibodies to the IL-2 receptor, in which either a chimeric protein has been made between mouse Fab with human Fc (basiliximab) or "humanized" by splicing the combining sites of the mouse into a molecule that is 90% human IgG (daclizumab), have been approved for prophylaxis of acute rejection in the immediate posttransplant period. They are effective at decreasing the acute rejection rate and have few adverse side effects.

CLINICAL COURSE AND MANAGEMENT OF THE RECIPIENT

Adequate hemodialysis should be performed within 48 h of surgery, and care should be taken that the serum potassium level is not markedly elevated so that intraoperative cardiac arrhythmias can be averted. The diuresis that commonly occurs postoperatively must be carefully monitored; in some instances it may be massive, reflecting the inability of ischemic tubules to regulate sodium and water excretion; with large diureses, massive potassium losses may occur. Most chronically uremic patients have some excess of extracellular fluid, and it is useful to maintain an expanded fluid volume in the immediate postoperative period. Acute tubular necrosis (ATN) may cause immediate oliguria or may follow an initial short period of graft function. ATN is most likely when cadaveric donors have been hypotensive or if the interval between cessation of blood flow and organ harvest (warm ischemic time) is more than a few minutes. Recovery usually occurs within 3 weeks, although periods as long as 6 weeks have been reported. Superimposition of rejection on ATN is common, and the differential diagnosis may be difficult without a graft biopsy. Cyclosporine therapy prolongs ATN, and some patients do not diurese until the dose is drastically reduced. Many centers avoid starting cyclosporine for the first several days, using ALG4 or a monoclonal antibody along with mycophenolate mofetil and prednisone until renal function is established. Fig. 263-3 illustrates an algorithm followed by many transplant centers for early posttransplant management of recipients at high or low risk of early renal dysfunction.

The Rejection Episode Early diagnosis of rejection allows prompt institution of therapy to preserve renal function and prevent irreversible damage. Clinical evidence of rejection is rarely characterized by fever, swelling, and tenderness over the allograft. Rejection may present only with a rise in serum creatinine, with or without a reduction in urine volume. The focus should be on ruling out other causes of functional deterioration.

Arteriography and radioactive iodohippurate sodium renograms of the transplanted kidney may be useful in ascertaining changes in the renal vasculature and in renal blood flow, even in the absence of urinary flow. Thrombosis of the renal vein occurs rarely; it may be reversible if caused by technical factors and intervention is prompt. Diagnostic ultrasound is the procedure of choice to rule out urinary obstruction or to confirm the presence of perirenal collections of urine, blood, or lymph. When renal function has been good initially, a rise in the serum creatinine level is the most sensitive and reliable indicator of possible rejection and may be the only sign.

Calcineurin inhibitors (cyclosporine or tacrolimus) may cause deterioration in renal function in a manner similar to a rejection episode. In fact, rejection processes tend to be more indolent with these inhibitors, and the only way to make a diagnosis may be by renal biopsy. Calcineurin inhibitors have an afferent arteriolar constrictor effect on the kidney and may produce permanent vascular and interstitial injury after sustained high-dose therapy. Addition of angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs are likely to raise serum creatinine levels. The former are generally safe to use after the early months, while the latter are best avoided in all renal transplant patients. There is no universally accepted lesion(s) that makes a diagnosis of calcineurin inhibitor toxicity, although interstitial fibrosis, isometric tubular vacuolization, and thickening of arteriolar walls have been noted by some. Basically, if the biopsy does not reveal moderate and active cellular rejection activity, the serum creatinine will most likely respond to a reduction in dose. Blood levels of drug can be useful if very high or very low but do not correlate precisely with renal function, although serial changes in a patient can be useful. If rejection activity is present in the biopsy, appropriate therapy is indicated. The first rejection episode is usually treated with intravenous administration of methylprednisolone, 500 to 1000 mg daily for 3 days. Failure to respond is indication for antibody therapy, usually with OKT3.

OKT3 monoclonal antibody, given intravenously for 10 to 14 days, is effective in 90% of first rejections but less so if methylprednisolone pulses have failed and in cases of severe recurrent rejection activity. A major problem with OKT3 is that severe systemic reactions may be produced during the first day or two of therapy. Chills, fever, hypotension, and headache are the direct result of the antibody effects on the targeted T cells, most likely related to the known potential of OKT3 to activate T cells nonspecifically with release of cytokines, especially tumor necrosis factor a. If the antibody is administered to overhydrated oliguric patients, pulmonary edema may be induced. These reactions are not characteristic of other monoclonal antibodies, such as those to the IL3-2 receptor. Recurrent or rebound rejection activity may require additional therapy. In such circumstances, methylprednisolone may be effective even though it failed initially. Second courses of OKT3 may be given in spite of HAMA5 generated in response to the first course if the titers are low and the human antibodies are not directed to the combining-site region (idiotype) of the OKT3.

Management Problems The usual clinical manifestations of infection in the posttransplant period are blunted by immunosuppressive therapy. The major toxic effect of azathioprine is bone marrow suppression, which is less likely with mycophenolate mofetil, while calcineurin inhibitors have no marrow effects. All drugs predispose to unusual opportunistic infections, however. The typical times posttransplant when the most common opportunistic infections occur are tabulated in Table 263-3. The signs and symptoms of infection may be masked or distorted. Fever without obvious cause is common and only after days or weeks may it become apparent that it has a viral or fungal origin. Bacterial infections are most common during the first month after transplantation. The importance of blood cultures in such patients cannot be overemphasized, because systemic infection without obvious foci is frequent, although wound infections with or without urinary fistulas are most common. Particularly ominous are rapidly occurring pulmonary lesions, which may result in death within 5 days of onset. When these become apparent, immunosuppressive agents should be discontinued, except for maintenance doses of prednisone.

Aggressive diagnostic procedures, including transbronchial and open lung biopsy, are frequently indicated. In the case of Pneumocystis carinii (Chap. 191) infection, trimethoprim-sulfamethoxazole is the treatment of choice; amphotericin B has been used effectively in systemic fungal infections. Prophylaxis against P. carinii with daily or alternate day low-dose trimethoprim-sulfamethoxazole is very effective. Involvement of the oropharynx with Candida (Chap. 187) may be treated with local nystatin. Tissue-invasive fungal infections require treatment with systemic agents such as fluconazole. Small doses (a total of 300 mg) of amphotericin given over a period of 2 weeks may be effective in fungal infections refractory to fluconazole. Macrolide antibiotics, especially ketoconazole and erythromycin, and some calcium channel blockers (diltiazem, verapamil) compete with calcineurin inhibitors for P450 catabolism and cause elevated levels of these immunosuppressive drugs. Analeptics, such as phenytoin and carbamazepine, will increase catabolism to result in low levels. Aspergillus (Chap. 188), Nocardia (Chap. 146), and cytomegalovirus (CMV) (Chap. 166) infections also occur.

CMV6 is a common and dangerous infection in transplant recipients. It does not generally appear until the end of the first posttransplant month. Active CMV infection is sometimes associated, or occasionally confused, with rejection episodes. Patients at highest risk for severe CMV disease are those without anti-CMV antibodies who receive a graft from a CMV antibody-positive donor (15% mortality). Serial intravenous administration of high-titer CMV immune globulin is effective in reducing this risk. Prophylactic use of ganciclovir is an effective alternative. Valganciclovir is a cost-effective and bioavailable oral form of ganciclovir that has proven effective in both prophylaxis and treatment of CMV disease. Early diagnosis in a febrile patient can be made by detecting CMV antigens in the blood. A rise in IgM antibodies to CMV is also diagnostic. Culture of CMV from blood may be less sensitive. Tissue invasion of CMV is common in the gastrointestinal tract and lungs. CMV retinopathy occurs late in the course, if untreated. Treatment of active CMV disease with valganciclovir is always indicated. Many patients immune to CMV can activate the virus after heavy immunosuppression, such as with OKT3. Concurrent treatment with ganciclovir during OKT3 administration appears to be effective for prophylaxis of CMV activation. The complications of glucocorticoid therapy are well known and include gastrointestinal bleeding, impairment of wound healing, osteoporosis, diabetes mellitus, cataract formation, and hemorrhagic pancreatitis. The treatment of unexplained jaundice in transplant patients should include cessation or reduction of immunosuppressive drugs if hepatitis or drug toxicity is suspected. It is surprising that cessation of azathioprine or calcineurin inhibitor therapy in such circumstances often does not result in rejection of a graft, at least for several weeks. Acyclovir is effective in therapy of herpes simplex virus infections.

Chronic Lesions of the Transplanted Kidney While 1-year transplant survival is excellent, most recipients experience progressive decline in kidney function over time thereafter. The chronic renal transplant dysfunction can be caused by recurrent disease, hypertension, cyclosporine or tacrolimus nephrotoxicity, chronic immunologic rejection, secondary focal glomerulosclerosis, or a combination of these pathophysiologies. Chronic vascular changes with intimal proliferation and medical hypertrophy are commonly found. Control of systemic and intrarenal hypertension with ACE7 inhibitors is thought to have a beneficial influence on the rate of progression of chronic renal transplant dysfunction. Renal biopsy can distinguish subacute cellular rejection from recurrent disease or secondary focal sclerosis.

Malignancy The incidence of tumors in patients on immunosuppressive therapy is 5 to 6%, or approximately 100 times greater than that in the general population of the same age range. The most common lesions are cancer of the skin and lips and carcinoma in situ of the cervix, as well as lymphomas, such as non-Hodgkin's lymphomas. The risks are increased in proportion to the total immunosuppressive load administered and time elapsed since transplantation. Surveillance for skin and cervical cancers is necessary.

Other Complications Hypercalcemia after transplantation may indicate failure of hyperplastic parathyroid glands to regress. Aseptic necrosis of the head of the femur is probably due to preexisting hyperparathyroidism, with aggravation by glucocorticoid treatment. With improved management of calcium and phosphorus metabolism during chronic dialysis, the incidence of parathyroid-related complications has fallen dramatically. Persistent hyperparathyroid activity may require subtotal parathyroidectomy.

Hypertension may be caused by (1) native kidneys; (2) rejection activity in the transplant; (3) renal artery stenosis, if an end-to-end anastomosis was constructed with an iliac artery branch; and (4) renal calcineurin inhibitor toxicity. The latter may improve with reduction in dose. Whereas ACE8 inhibitors may be useful, calcium channel blockers are more frequently used initially. Amelioration of hypertension to the 120 to 130/70 to 80 mmHg range should be the goal in all patients.

While most transplant patients have a robust production of erythropoietin and normalization of the hemoglobin without exogenous erythropoietin administration, anemia is commonly seen in the posttransplant period. Often the anemia is attributable to bone marrow-suppressant immunosuppressive medications such as azathioprine, mycophenolate mofetil, or sirolimus. Gastrointestinal bleeding is a common side effect of high-dose and long-term steroid administration. Many transplant patients have creatinine clearances of 30 to 50 mL/min and can be considered in the same way as other patients with chronic renal insufficiency for anemia management, including supplemental erythropoietin.

Chronic hepatitis, particularly when due to hepatitis B virus, can be a progressive, fatal disease over a decade or so. Patients who are persistently hepatitis B surface antigen-positive are at higher risk, according to some studies, but the presence of hepatitis C virus is also a concern when one embarks on a course of immunosuppression in a transplant recipient.

Both chronic dialysis and renal transplant patients have a higher incidence of death from myocardial infarction and stroke than in the population at large, and this is particularly true in diabetic patients. Contributing factors are the use of glucocorticoids, hypertension, and hypertriglyceridemia. Increased low-density lipoprotein cholesterol and depressed high-density lipoprotein cholesterol concentrations may be exaggerated after transplantation and require treatment, particularly in patients receiving sirolimus. Recipients of renal transplants have a high prevalence of coronary artery and peripheral vascular diseases. The percentage of deaths from these causes has been slowly rising as the numbers of transplanted diabetic patients and the average age of all recipients increase. More than 50% of renal recipient mortality is attributable to cardiovascular disease. In addition to strict control of blood pressure and blood lipid levels, close monitoring of patients for indications of further medical or surgical intervention is an important part of management.


	5. UTI

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URINARY TRACT INFECTIONS AND PYELONEPHRITIS - Walter E. Stamm

DEFINITIONS

Acute infections of the urinary tract can be subdivided into two general anatomic categories: lower tract infection (urethritis and cystitis) and upper tract infection (acute pyelonephritis, prostatitis, and intrarenal and perinephric abscesses). Infections at these various sites may occur together or independently and may either be asymptomatic or present as one of the clinical syndromes described below. Infections of the urethra and bladder are often considered superficial (or mucosal) infections, while prostatitis, pyelonephritis, and renal suppuration signify tissue invasion.

From a microbiologic perspective, urinary tract infection (UTI) exists when pathogenic microorganisms are detected in the urine, urethra, bladder, kidney, or prostate. In most instances, growth of 105 organisms per milliliter from a properly collected midstream "clean-catch" urine sample indicates infection. However, significant bacteriuria is lacking in some cases of true UTI. Especially in symptomatic patients, a smaller number of bacteria (102 to 104/mL) may signify infection. In urine specimens obtained by suprapubic aspiration or "in-and-out" catheterization and in samples from a patient with an indwelling catheter, colony counts of 102 to 104/mL generally indicate infection. Conversely, colony counts of 105/mL of midstream urine are occasionally due to specimen contamination, which is especially likely when multiple bacterial species are found.

Infections that recur after antibiotic therapy can be due to the persistence of the originally infecting strain (as judged by species, antibiogram, serotype, and molecular type) or to reinfection with a new strain. "Same-strain" recurrent infections that become evident within 2 weeks of cessation of therapy can be the result of unresolved renal or prostatic infection (termed relapse) or of persistent vaginal or intestinal colonization leading to rapid reinfection of the bladder.

Symptoms of dysuria, urgency, and frequency that are unaccompanied by significant bacteriuria have been termed the acute urethral syndrome. Although widely used, this term lacks anatomic precision because many cases so designated are actually bladder infections. Moreover, since the causative agent can usually be identified in these patients, the term syndrome — implying unknown causation — is inappropriate.

Chronic pyelonephritis refers to chronic interstitial nephritis believed to result from bacterial infection of the kidney (Chap. 266). Many noninfectious diseases also cause an interstitial nephritis that is indistinguishable pathologically from chronic pyelonephritis.

ACUTE UTIS1: URETHRITIS, CYSTITIS, AND PYELONEPHRITIS

EPIDEMIOLOGY

Epidemiologically, UTIs1 are subdivided into catheter-associated (or nosocomial) infections and non-catheter-associated (or community-acquired) infections. Infections in either category may be symptomatic or asymptomatic. Acute community-acquired infections are very common and account for more than 7 million office visits annually in the United States. These infections occur in 1 to 3% of schoolgirls and then increase markedly in incidence with the onset of sexual activity in adolescence. The vast majority of acute symptomatic infections involve young women; a prospective study demonstrated an annual incidence of 0.5 to 0.7 infections per patient-year in this group. Acute symptomatic UTIs are unusual in men under the age of 50. The development of asymptomatic bacteriuria parallels that of symptomatic infection and is rare among men under 50 but common among women between 20 and 50. Asymptomatic bacteriuria is more common among elderly men and women, with rates as high as 40 to 50% in some studies.

ETIOLOGY

Many different microorganisms can infect the urinary tract, but by far the most common agents are the gram-negative bacilli. Escherichia coli causes ~80% of acute infections in patients without catheters, urologic abnormalities, or calculi. Other gram-negative rods, especially Proteus and Klebsiella and occasionally Enterobacter, account for a smaller proportion of uncomplicated infections. These organisms, plus Serratia and Pseudomonas, assume increasing importance in recurrent infections and in infections associated with urologic manipulation, calculi, or obstruction. They play a major role in nosocomial, catheter-associated infections (see below). Proteus spp., by virtue of urease production, and Klebsiella spp., through the production of extracellular slime and polysaccharides, predispose to stone formation and are isolated more frequently from patients with calculi.

Gram-positive cocci play a lesser role in UTIs1. However, Staphylococcus saprophyticus — a novobiocin-resistant, coagulase-negative species — accounts for 10 to 15% of acute symptomatic UTIs in young females. Enterococci occasionally cause acute uncomplicated cystitis in women. More commonly, enterococci and Staphylococcus aureus cause infections in patients with renal stones or previous instrumentation or surgery. Isolation of S. aureus from the urine should arouse suspicion of bacteremic infection of the kidney.

About one-third of women with dysuria and frequency have either an insignificant number of bacteria in midstream urine cultures or completely sterile cultures and have been previously defined as having the urethral syndrome. About three-quarters of these women have pyuria, while one-quarter have no pyuria and little objective evidence of infection. In the women with pyuria, two groups of pathogens account for most infections. Low counts (102 to 104/mL) of typical bacterial uropathogens such as E. coli, S. saprophyticus, Klebsiella, or Proteus are found in midstream urine specimens from most of these women. These bacteria are probably the causative agents in these infections because they can usually be isolated from a suprapubic aspirate, are associated with pyuria, and respond to appropriate antimicrobial therapy. In other women with acute urinary symptoms, pyuria, and urine that is sterile (even when obtained by suprapubic aspiration), sexually transmitted urethritis-producing agents such as Chlamydia trachomatis, Neisseria gonorrhoeae, and herpes simplex virus are etiologically important. These agents are found most frequently in young, sexually active women with new sexual partners.

The causative role of several more unusual bacterial and nonbacterial pathogens in UTIs1 remains poorly defined. Ureaplasma urealyticum has frequently been isolated from the urethra and urine of patients with acute dysuria and frequency but is also found in specimens from many patients without urinary symptoms. Ureaplasmas probably account for some cases of urethritis and cystitis. U. urealyticum and Mycoplasma hominis have been isolated from prostatic and renal tissues of patients with acute prostatitis and pyelonephritis, respectively, and are probably responsible for some of these infections as well. Adenoviruses cause acute hemorrhagic cystitis in children and in some young adults, often in epidemics. Although other viruses can be isolated from urine (e.g., cytomegalovirus), they are thought not to cause acute UTI. Colonization of the urine of catheterized or diabetic patients by Candida and other fungal species is common and sometimes progresses to symptomatic invasive infection (Chap. 187). Mycobacterial infection of the genitourinary tract is discussed in Chap. 150.

PATHOGENESIS AND SOURCES OF INFECTION

The urinary tract should be viewed as a single anatomic unit that is united by a continuous column of urine extending from the urethra to the kidney. In the vast majority of UTIs1, bacteria gain access to the bladder via the urethra. Ascent of bacteria from the bladder may follow and is probably the pathway for most renal parenchymal infections.

The vaginal introitus and distal urethra are normally colonized by diphtheroids, streptococcal species, lactobacilli, and staphylococcal species but not by the enteric gram-negative bacilli that commonly cause UTIs1. In females prone to the development of cystitis, however, enteric gram-negative organisms residing in the bowel colonize the introitus, the periurethral skin, and the distal urethra before and during episodes of bacteriuria. The factors that predispose to periurethral colonization with gram-negative bacilli remain poorly understood, but alteration of the normal vaginal flora by antibiotics, other genital infections, or contraceptives (especially spermicide) appears to play an important role. Loss of the normally dominant H2O2-producing lactobacilli in the vaginal flora appears to facilitate colonization by E. coli. Small numbers of periurethral bacteria probably gain entry to the bladder frequently, a process that is facilitated in some cases by urethral massage during intercourse. Whether bladder infection ensues depends on interacting effects of the pathogenicity of the strain, the inoculum size, and the local and systemic host defense mechanisms.

Under normal circumstances, bacteria placed in the bladder are rapidly cleared, partly through the flushing and dilutional effects of voiding but also as a result of the antibacterial properties of urine and the bladder mucosa. Owing mostly to a high urea concentration and high osmolarity, the bladder urine of many normal persons inhibits or kills bacteria. Prostatic secretions possess antibacterial properties as well. Polymorphonuclear leukocytes enter the bladder epithelium and the urine soon after infection arises and play a role in clearing bacteriuria. The role of locally produced antibody remains unclear.

Hematogenous pyelonephritis occurs most often in debilitated patients who are either chronically ill or receiving immunosuppressive therapy. Metastatic staphylococcal or candidal infections of the kidney may follow bacteremia or fungemia, spreading from distant foci of infection in the bone, skin, vasculature, or elsewhere.

CONDITIONS AFFECTING PATHOGENESIS

Gender and Sexual Activity The female urethra appears to be particularly prone to colonization with colonic gram-negative bacilli because of its proximity to the anus, its short length (~4 cm), and its termination beneath the labia. Sexual intercourse causes the introduction of bacteria into the bladder and is temporally associated with the onset of cystitis; it thus appears to be important in the pathogenesis of UTIs1 in younger women. Voiding after intercourse reduces the risk of cystitis, probably because it promotes the clearance of bacteria introduced during intercourse. Use of spermicidal compounds with a diaphragm or cervical cap or use of spermicide-coated condoms dramatically alters the normal introital bacterial flora and has been associated with marked increases in vaginal colonization with E. coli and in the risk of UTI.

In males who are 50 years old and who have no history of heterosexual or homosexual rectal intercourse, UTI1 is exceedingly uncommon, and this diagnosis should be questioned in the absence of clear documentation. An important factor predisposing to bacteriuria in men is urethral obstruction due to prostatic hypertrophy. Insertive rectal intercourse is also associated with an increased risk of cystitis in men. Men (and women) who are infected with HIV and who have CD4+ T cell counts of 200/uL are at increased risk of both bacteriuria and symptomatic UTI. Finally, lack of circumcision has been identified as a risk factor for UTI in both neonates and young men.

Pregnancy UTIs1 are detected in 2 to 8% of pregnant women. Symptomatic upper tract infections, in particular, are unusually common during pregnancy; fully 20 to 30% of pregnant women with asymptomatic bacteriuria subsequently develop pyelonephritis. This predisposition to upper tract infection during pregnancy results from decreased ureteral tone, decreased ureteral peristalsis, and temporary incompetence of the vesicoureteral valves. Bladder catheterization during or after delivery causes additional infections. Increased incidences of low-birth-weight infants, premature delivery, and newborn mortality result from UTIs during pregnancy, particularly those infections involving the upper tract.

Obstruction Any impediment to the free flow of urine — tumor, stricture, stone, or prostatic hypertrophy — results in hydronephrosis and a greatly increased frequency of UTI1. Infection superimposed on urinary tract obstruction may lead to rapid destruction of renal tissue. It is of utmost importance, therefore, when infection is present, to identify and repair obstructive lesions. On the other hand, when an obstruction is minor and is not progressive or associated with infection, great caution should be exercised in attempting surgical correction. The introduction of infection in such cases may be more damaging than an uncorrected minor obstruction that does not significantly impair renal function.

Neurogenic Bladder Dysfunction Interference with bladder enervation, as in spinal cord injury, tabes dorsalis, multiple sclerosis, diabetes, and other diseases, may be associated with UTI1. The infection may be initiated by the use of catheters for bladder drainage and is favored by the prolonged stasis of urine in the bladder. An additional factor often operative in these cases is bone demineralization due to immobilization, which causes hypercalciuria, calculus formation, and obstructive uropathy.

Vesicoureteral Reflux Defined as reflux of urine from the bladder cavity up into the ureters and sometimes into the renal pelvis, vesicoureteral reflux occurs during voiding or with elevation of pressure in the bladder. In practice, this condition is demonstrated by the finding of retrograde movement of radiopaque or radioactive material during a voiding cystourethrogram. An anatomically impaired vesicoureteral junction facilitates reflux of bacteria and thus upper tract infection. However, since a fluid connection between the bladder and the kidney always exists, even in the normal urinary system, some retrograde movement of bacteria probably takes place during infection but is not detected by radiologic techniques.

Vesicoureteral reflux is common among children with anatomic abnormalities of the urinary tract as well as among children with anatomically normal but infected urinary tracts. In the latter group, reflux disappears with advancing age and is probably attributable to factors other than UTI1. Long-term follow-up of children with UTI who have reflux has established that renal damage correlates with marked reflux, not with infection.

The routine search for reflux would be aided by the development of noninvasive tests applicable to young children, in whom the need for an effective technique is greatest. In the meantime, it appears reasonable to search for reflux in anyone with unexplained failure of renal growth or with renal scarring, because UTI1 per se is an insufficient explanation for these abnormalities. On the other hand, it is doubtful that all children who have recurrent UTIs but whose urinary tract appears normal on pyelography should be subjected to voiding cystoureterography merely for the detection of the rare patient with marked reflux not revealed by the intravenous pyelogram.

Bacterial Virulence Factors Not all strains of E. coli are equally capable of infecting the intact urinary tract. Bacterial virulence factors markedly influence the likelihood that a given strain, once introduced into the bladder, will cause UTI1. Most E. coli strains that cause symptomatic UTIs in noncatheterized patients belong to a small number of specific O, K, and H serogroups. These uropathogenic clones have accumulated a number of virulence genes that are often closely linked on the bacterial chromosome in "virulence islands." Adherence of bacteria to uroepithelial cells is a critical first step in the initiation of infection. For both E. coli and Proteus, fimbriae (hairlike proteinaceous surface appendages) mediate the attachment of bacteria to specific receptors on epithelial cells. The attachment of bacteria to uroepithelial cells initiates a number of important events in the mucosal epithelial cell, including secretion of interleukin (IL) 6 and IL-8 (with subsequent chemotaxis of leukocytes to the bladder mucosa) and induction of apoptosis and epithelial cell desquamation. Besides fimbriae, uropathogenic E. coli strains usually produce hemolysin and aerobactin (a siderophore for scavenging iron) and are resistant to the bactericidal action of human serum. Nearly all E. coli strains causing acute pyelonephritis and most of those causing acute cystitis are uropathogenic. In contrast, infections in patients with structural or functional abnormalities of the urinary tract are generally caused by bacterial strains that lack these uropathogenic properties; the implication is that these properties are not needed for infection of the compromised urinary tract.

Genetic Factors Increasing evidence suggests that host genetic factors influence susceptibility to UTI1. A maternal history of UTI is more often found among women who have experienced recurrent UTIs than among controls. The number and type of receptors on uroepithelial cells to which bacteria may attach are at least in part genetically determined. Many of these structures are components of blood group antigens and are present on both erythrocytes and uroepithelial cells. For example, P fimbriae mediate attachment of E. coli to P-positive erythrocytes and are found on nearly all strains causing acute uncomplicated pyelonephritis. Conversely, P blood group-negative individuals, who lack these receptors, have a decreased likelihood of pyelonephritis. It has also been demonstrated that nonsecretors of blood group antigens are at increased risk of recurrent UTI; this predisposition may relate to a different profile of genetically determined glycolipids on uroepithelial cells. Mutations in host genes integral to the immune response (interferon ? receptors and others) may also affect susceptibility to UTI.

LOCALIZATION OF INFECTION

Unfortunately, currently available methods of distinguishing renal parenchymal infection from cystitis are neither reliable nor convenient enough for routine clinical use. Fever or an elevated level of C-reactive protein often accompanies acute pyelonephritis and is found in rare cases of cystitis but also occurs in infections other than pyelonephritis.

CLINICAL PRESENTATION

Cystitis Patients with cystitis usually report dysuria, frequency, urgency, and suprapubic pain. The urine often becomes grossly cloudy and malodorous, and it is bloody in ~30% of cases. White cells and bacteria can be detected by examination of unspun urine in most cases. However, some women with cystitis have only 102 to 104 bacteria per milliliter of urine, and in these instances bacteria cannot be seen in a Gram-stained preparation of unspun urine. Physical examination generally reveals only tenderness of the urethra or the suprapubic area. If a genital lesion or a vaginal discharge is evident, especially in conjunction with 105 bacteria per milliliter on urine culture, then pathogens that may cause urethritis, vaginitis, or cervicitis, such as C. trachomatis, N. gonorrhoeae, Trichomonas, Candida, and herpes simplex virus, should be considered. Prominent systemic manifestations, such as a temperature of 38.3°C (101°F), nausea, and vomiting, usually indicate concomitant renal infection, as does costovertebral angle tenderness. However, the absence of these findings does not ensure that infection is limited to the bladder and urethra.

Acute Pyelonephritis Symptoms of acute pyelonephritis generally develop rapidly over a few hours or a day and include a fever, shaking chills, nausea, vomiting, and diarrhea. Symptoms of cystitis may or may not be present. Besides fever, tachycardia, and generalized muscle tenderness, physical examination reveals marked tenderness on deep pressure in one or both costovertebral angles or on deep abdominal palpation. In some patients, signs and symptoms of gram-negative sepsis predominate. Most patients have significant leukocytosis and bacteria detectable in Gram-stained unspun urine. Leukocyte casts are present in the urine of some patients, and the detection of these casts is pathognomonic. Hematuria may be demonstrated during the acute phase of the disease; if it persists after acute manifestations of infection have subsided, a stone, a tumor, or tuberculosis should be considered.

Except in individuals with papillary necrosis, abscess formation, or urinary obstruction, the manifestations of acute pyelonephritis usually respond to therapy within 48 to 72 h. However, despite the absence of symptoms, bacteriuria or pyuria may persist. In severe pyelonephritis, fever subsides more slowly and may not disappear for several days, even after appropriate antibiotic treatment has been instituted.

Urethritis Approximately 30% of women with acute dysuria, frequency, and pyuria have midstream urine cultures that show either no growth or insignificant bacterial growth. Clinically, these women cannot always be readily distinguished from those with cystitis. In this situation, a distinction should be made between women infected with sexually transmitted pathogens, such as C. trachomatis, N. gonorrhoeae, or herpes simplex virus, and those with low-count E. coli or staphylococcal infection of the urethra and bladder. Chlamydial or gonococcal infection should be suspected in women with a gradual onset of illness, no hematuria, no suprapubic pain, and 7 days of symptoms. The additional history of a recent sex-partner change, especially if the patient's partner has recently had chlamydial or gonococcal urethritis, should heighten the suspicion of a sexually transmitted infection, as should the finding of mucopurulent cervicitis (Chap. 115). Gross hematuria, suprapubic pain, an abrupt onset of illness, a duration of illness of 3 days, and a history of UTIs1 favor the diagnosis of E. coli UTI.

Catheter-Associated UTIs1 (See also Chap. 116) Bacteriuria develops in at least 10 to 15% of hospitalized patients with indwelling urethral catheters. The risk of infection is ~3 to 5% per day of catheterization. E. coli, Proteus, Pseudomonas, Klebsiella, Serratia, staphylococci, enterococci, and Candida usually cause these infections. Many infecting strains display markedly greater antimicrobial resistance than organisms that cause community-acquired UTIs1. Factors associated with an increased risk of catheter-associated UTI include female sex, prolonged catheterization, severe underlying illness, disconnection of the catheter and drainage tube, other types of faulty catheter care, and lack of systemic antimicrobial therapy.

Infection occurs when bacteria reach the bladder by one of two routes: by migrating through the column of urine in the catheter lumen (intraluminal route) or by moving up the mucous sheath outside the catheter (periurethral route). Hospital-acquired pathogens reach the patient's catheter or urine-collecting system on the hands of hospital personnel, in contaminated solutions or irrigants, and via contaminated instruments or disinfectants. Bacteria usually enter the catheter system at the catheter-collecting tube junction or at the drainage bag portal. The organisms then ascend intraluminally into the bladder within 24 to 72 h. Alternatively, the patient's own bowel flora may colonize the perineal skin and periurethral area and reach the bladder via the external surface of the catheter. This route is particularly common in women. Studies have demonstrated the importance of the attachment and growth of bacteria on the surfaces of the catheter in the pathogenesis of catheter-associated UTI1. Such bacteria growing in biofilms on the catheter eventually produce encrustations consisting of bacteria, bacterial glycocalyces, host urinary proteins, and urinary salts. These encrustations provide a refuge for bacteria and may protect them from antimicrobial agents and phagocytes.

Clinically, most catheter-associated infections cause minimal symptoms and no fever and often resolve after withdrawal of the catheter. The frequency of upper tract infection associated with catheter-induced bacteriuria is unknown. Gram-negative bacteremia, which follows catheter-associated bacteriuria in 1 to 2% of cases, is the most significant recognized complication of catheter-induced UTIs1. The catheterized urinary tract has repeatedly been demonstrated to be the most common source of gram-negative bacteremia in hospitalized patients, generally accounting for ~30% of cases.

Catheter-associated UTIs1 can sometimes be prevented in patients catheterized for 2 weeks by use of a sterile closed collecting system, by attention to aseptic technique during insertion and care of the catheter, and by measures to minimize cross-infection. Other preventive approaches, including short courses of systemic antimicrobial therapy, topical application of periurethral antimicrobial ointments, use of preconnected catheter-drainage tube units, use of catheters impregnated with antimicrobial agents, and addition of antimicrobial drugs to the drainage bag, have all been protective in at least one controlled trial but are not recommended for general use. Despite precautions, the majority of patients catheterized for 2 weeks eventually develop bacteriuria. For example, because of spinal cord injury, incontinence, or other factors, some patients in hospitals or nursing homes require long-term or semipermanent bladder catheterization. Measures intended to prevent infection have been largely unsuccessful, and essentially all such chronically catheterized patients develop bacteriuria. If feasible, intermittent catheterization by a nurse or by the patient appears to reduce the incidence of bacteriuria and associated complications in such patients. Treatment should be provided when symptomatic infections arise, but treatment of asymptomatic bacteriuria in such patients has no apparent benefit.

DIAGNOSTIC TESTING

Determination of the number and type of bacteria in the urine is an extremely important diagnostic procedure. In symptomatic patients, bacteria are usually present in the urine in large numbers (=105/mL). In asymptomatic patients, two consecutive urine specimens should be examined bacteriologically before therapy is instituted, and =105 bacteria of a single species per milliliter should be demonstrable in both specimens. Since the large number of bacteria in the bladder urine is due in part to bacterial multiplication during residence in the bladder cavity, samples of urine from the ureters or renal pelvis may contain 105 bacteria per milliliter and yet indicate infection. Similarly, the presence of bacteriuria of any degree in suprapubic aspirates or of =102 bacteria per milliliter of urine obtained by catheterization usually indicates infection. In some circumstances (antibiotic treatment, high urea concentration, high osmolarity, low pH), urine inhibits bacterial multiplication, resulting in relatively low bacterial colony counts despite infection. For this reason, antiseptic solutions should not be used in washing the periurethral area before collection of the urine specimen. Water diuresis or recent voiding also reduces bacterial counts in urine.

Microscopy of urine from symptomatic patients can be of great diagnostic value. Microscopic bacteriuria, which is best assessed with Gram-stained uncentrifuged urine, is found in 90% of specimens from patients whose infections are associated with colony counts of at least 105/mL, and this finding is very specific. However, bacteria cannot usually be detected microscopically in infections with lower colony counts (102 to 104/mL). The detection of bacteria by urinary microscopy thus constitutes firm evidence of infection, but the absence of microscopically detectable bacteria does not exclude the diagnosis. When carefully sought by means of chamber-count microscopy, pyuria is a highly sensitive indicator of UTI1 in symptomatic patients. Pyuria is demonstrated in nearly all acute bacterial UTIs, and its absence calls the diagnosis into question. The leukocyte esterase "dipstick" method is less sensitive than microscopy in identifying pyuria but is a useful alternative where microscopy is not feasible. Pyuria in the absence of bacteriuria (sterile pyuria) may indicate infection with unusual bacterial agents such as C. trachomatis, U. urealyticum, and Mycobacterium tuberculosis or with fungi. Alternatively, sterile pyuria may be demonstrated in noninfectious urologic conditions such as calculi, anatomic abnormality, nephrocalcinosis, vesicoureteral reflux, interstitial nephritis, or polycystic disease.

Although many authorities have recommended that urine culture and antimicrobial susceptibility testing be performed for any patient with a suspected UTI1, it may be more practical and cost-effective to manage women who have symptoms characteristic of acute uncomplicated cystitis without an initial urine culture. Two approaches to presumptive therapy have generally been used. In the first, treatment is initiated solely on the basis of a typical history and/or typical findings on physical examination. In the second, women with symptoms and signs of acute cystitis and without complicating factors are managed with urinary microscopy (or, alternatively, with a leukocyte esterase test). A positive result for pyuria and/or bacteriuria provides enough evidence of infection to indicate that urine culture and susceptibility testing can be omitted and the patient treated empirically. Urine should be cultured, however, when a woman's symptoms and urine-examination findings leave the diagnosis of cystitis in question. Pretherapy cultures and susceptibility testing are also essential in the management of all patients with suspected upper tract infections and of those with complicating factors, as in these situations any of a variety of pathogens may be involved and antibiotic therapy is best tailored to the individual organism.

TREATMENT

The following principles underlie the treatment of UTIs1:

1. Except in acute uncomplicated cystitis in women, a quantitative urine culture or a comparable alternative diagnostic test should be performed to confirm infection before empirical treatment is begun. When culture results become available, antimicrobial sensitivity testing should be used to further direct therapy.

2. Factors predisposing to infection, such as obstruction and calculi, should be identified and corrected if possible.

3. Relief of clinical symptoms does not always indicate bacteriologic cure.

4. Each course of treatment should be classified after its completion as a failure (symptoms and/or bacteriuria not eradicated during therapy or in the immediate posttreatment culture) or a cure (resolution of symptoms and elimination of bacteriuria). Recurrent infections should be classified as same-strain or different-strain and as early (occurring within 2 weeks of the end of therapy) or late.

5. In general, uncomplicated infections confined to the lower urinary tract respond to short courses of therapy, while upper tract infections require longer treatment. After therapy, early recurrences due to the same strain may result from an unresolved upper tract focus of infection but often (especially after short-course therapy for cystitis) result from persistent vaginal colonization. Recurrences 2 weeks after the cessation of therapy nearly always represent reinfection with a new strain or with the previously infecting strain that has persisted in the vaginal and rectal flora.

6. Despite increasing resistance, community-acquired infections, especially initial infections, are usually due to more antibiotic-sensitive strains.

7. In patients with repeated infections, instrumentation, or recent hospitalization, the presence of antibiotic-resistant strains should be suspected. Although many antimicrobial agents reach high concentrations in urine, in vitro resistance usually predicts a substantially higher failure rate.

The anatomic location of a UTI1 greatly influences the success or failure of a therapeutic regimen. Bladder bacteriuria (cystitis) can usually be eliminated with nearly any antimicrobial agent to which the infecting strain is sensitive; in the past, it was demonstrated that as little as a single dose of 500 mg of intramuscular kanamycin eliminated bladder bacteriuria in most cases. With upper tract infections, however, single-dose therapy fails in the majority of cases, and even a 7-day course is unsuccessful in many instances. Longer periods of treatment (2 to 6 weeks) aimed at eradicating a persistent focus of infection may be necessary in some cases.

In acute uncomplicated cystitis, more than 90 to 95% of infections are due to one of two organisms: E. coli or S. saprophyticus. Although resistance patterns vary geographically and resistance has increased in many areas, most strains are sensitive to many antibiotics. In most parts of the United States, more than one-quarter of E. coli strains causing acute cystitis are resistant to amoxicillin, sulfa drugs, and cephalexin; resistance to trimethoprim (TMP) and trimethoprim-sulfamethoxazole (TMP-SMX) is now approaching these levels as well in many areas. Substantially higher rates of resistance to TMP-SMX have been documented in some other countries, as has resistance to fluoroquinolones.

Many have advocated single-dose treatment for acute cystitis. The advantages of single-dose therapy include less expense, ensured compliance, fewer side effects, and perhaps less intense pressure favoring the selection of resistant organisms in the intestinal, vaginal, or perineal flora. However, more frequent recurrences develop shortly after single-dose therapy than after 3-day treatment, and single-dose therapy does not eradicate vaginal colonization with E. coli as effectively as do longer regimens. A 3-day course of therapy with TMP-SMX2, TMP3, norfloxacin, ciprofloxacin, or ofloxacin appears to preserve the low rate of side effects of single-dose therapy while improving efficacy (Table 269-1); thus 3-day regimens are currently preferred for acute cystitis. In areas where TMP-SMX resistance exceeds 20%, either a fluoroquinolone or nitrofurantoin can be used (Table 269-1). Neither single-dose nor 3-day therapy should be used for women with symptoms or signs of pyelonephritis, urologic abnormalities or stones, or previous infections due to antibiotic-resistant organisms. Males with UTI1 often have urologic abnormalities or prostatic involvement and hence are not candidates for single-dose or 3-day therapy. For empirical therapy, they should generally receive a 7- to 14-day course of a fluoroquinolone (Table 269-1).

The choice of treatment for women with acute urethritis depends on the etiologic agent involved. In chlamydial infection, azithromycin (1 g in a single oral dose) or doxycycline (100 mg twice daily by mouth for 7 days) should be used. Women with acute dysuria and frequency, negative urine cultures, and no pyuria usually do not respond to antimicrobial agents.

In women, acute uncomplicated pyelonephritis without accompanying clinical evidence of calculi or urologic disease is due to E. coli in most cases. Although the optimal route and duration of therapy have not been established, a 7- to 14-day course of a fluoroquinolone, an aminoglycoside, or a third-generation cephalosporin is usually adequate. Neither ampicillin nor TMP-SMX4 should be used as initial therapy because 25% of strains of E. coli causing pyelonephritis are now resistant to these drugs in vitro. For at least the first few days of treatment, antibiotics should probably be given intravenously to most patients, but patients with mild symptoms can be treated for 7 to 14 days with an oral antibiotic (usually ciprofloxacin or ofloxacin), with or without an initial single parenteral dose (Table 269-1). Patients who fail to respond to treatment within 72 h or who relapse after therapy should be evaluated for unrecognized suppurative foci, calculi, or urologic disease.

Complicated UTIs1 (those arising in a setting of catheterization, instrumentation, urologic anatomic or functional abnormalities, stones, obstruction, immunosuppression, renal disease, or diabetes) are typically due to hospital-acquired bacteria, including E. coli, Klebsiella, Proteus, Serratia, Pseudomonas, enterococci, and staphylococci. Many of the infecting strains are antibiotic-resistant. Empirical antibiotic therapy ideally provides broad-spectrum coverage against these pathogens. In patients with minimal or mild symptoms, oral therapy with a fluoroquinolone, such as ciprofloxacin or ofloxacin, can be administered until culture results and antibiotic sensitivities are known. In patients with more severe illness, including acute pyelonephritis or suspected urosepsis, hospitalization and parenteral therapy should be undertaken. Commonly used empirical regimens include imipenem alone, a penicillin or cephalosporin plus an aminoglycoside, and (when the involvement of enterococci is unlikely) ceftriaxone or ceftazidime. When information on the antimicrobial sensitivity pattern of the infecting strain becomes available, a more specific antimicrobial regimen can be selected. Therapy should generally be administered for 10 to 21 days, with the exact duration depending on the severity of the infection and the susceptibility of the infecting strain. Follow-up cultures 2 to 4 weeks after cessation of therapy should be performed to demonstrate cure.

The need for treatment as well as the optimal type and duration of treatment for catheterized patients with asymptomatic bacteriuria have not been established. Removal of the catheter in conjunction with a short course of antibiotics to which the organism is susceptible probably constitutes the best course of action and nearly always eradicates bacteriuria. Treatment of asymptomatic catheter-associated bacteriuria may be of greatest benefit to elderly women, who most often develop symptoms if left untreated. If the catheter cannot be removed, antibiotic therapy usually proves to be unsuccessful and may in fact result in infection with a more resistant strain. In this situation, the bacteriuria should be ignored unless the patient develops symptoms or is at high risk of developing bacteremia. In these cases, use of systemic antibiotics or urinary bladder antiseptics may reduce the degree of bacteriuria and the likelihood of bacteremia.

In pregnancy, acute cystitis can be managed with 7 days of treatment with amoxicillin, nitrofurantoin, or a cephalosporin. All pregnant women should be screened for asymptomatic bacteriuria during the first trimester and, if bacteriuric, should be treated with one of the regimens listed in Table 269-1. After treatment, a culture should be performed to ensure cure, and cultures should be repeated monthly thereafter until delivery. Acute pyelonephritis in pregnancy should be managed with hospitalization and parenteral antibiotic therapy, generally with a cephalosporin or an extended-spectrum penicillin. Continuous low-dose prophylaxis with nitrofurantoin should be given to women who have recurrent infections during pregnancy.

Asymptomatic bacteriuria in noncatheterized patients is common, especially among elderly patients, but has not been linked to adverse outcomes in most circumstances other than pregnancy. Thus antimicrobial therapy is unnecessary and may in fact promote the emergence of resistant strains in most patients with asymptomatic bacteriuria. High-risk patients with neutropenia, renal transplants, obstruction, or other complicating conditions may require treatment when asymptomatic bacteriuria occurs. Seven days of therapy with an oral agent to which the organism is sensitive should be given initially. If bacteriuria persists, it can be monitored without further treatment in most patients. Longer-term therapy (4 to 6 weeks) may be necessary in high-risk patients with persistent asymptomatic bacteriuria.

UROLOGIC EVALUATION

Very few women with recurrent UTIs1 have correctable lesions discovered at cystoscopy or upon intravenous pyelography, and these procedures should not be undertaken routinely in such cases. Urologic evaluation should be performed in selected instances — namely, in women with relapsing infection, a history of childhood infections, stones or painless hematuria, or recurrent pyelonephritis. Most males with UTI should be considered to have complicated infection and thus should be evaluated urologically. Possible exceptions include young men who have cystitis associated with sexual activity, who are uncircumcised, or who have AIDS. Men or women presenting with acute infection and signs or symptoms suggestive of an obstruction or stones should undergo prompt urologic evaluation, generally by means of ultrasound.

PROGNOSIS

In patients with uncomplicated cystitis or pyelonephritis, treatment ordinarily results in complete resolution of symptoms. Lower tract infections in women are of concern mainly because they cause discomfort, morbidity, loss of time from work, and substantial health care costs. Cystitis may also result in upper tract infection or in bacteremia (especially during instrumentation), but little evidence suggests that renal impairment follows. When repeated episodes of cystitis occur, they are more commonly reinfections rather than relapses.

Acute uncomplicated pyelonephritis in adults rarely progresses to renal functional impairment and chronic renal disease. Repeated upper tract infections often represent relapse rather than reinfection, and a vigorous search for renal calculi or an underlying urologic abnormality should be undertaken. If neither is found, 6 weeks of chemotherapy may be useful in eradicating an unresolved focus of infection.

Repeated symptomatic UTIs1 in children and in adults with obstructive uropathy, neurogenic bladder, structural renal disease, or diabetes progress to chronic renal disease with unusual frequency. Asymptomatic bacteriuria in these groups as well as in adults without urologic disease or obstruction predisposes to increased numbers of episodes of symptomatic infection but does not result in renal impairment in most instances.

PREVENTION

Women who experience frequent symptomatic UTIs1 (=3 per year on average) are candidates for long-term administration of low-dose antibiotics directed at preventing recurrences. Such women should be advised to avoid spermicide use and to void soon after intercourse. Daily or thrice-weekly administration of a single dose of TMP-SMX5 (80/400 mg), TMP6 alone (100 mg), or nitrofurantoin (50 mg) has been particularly effective. Norfloxacin and other fluoroquinolones have also been used for prophylaxis. Prophylaxis should be initiated only after bacteriuria has been eradicated with a full-dose treatment regimen. The same prophylactic regimens can be used after sexual intercourse to prevent episodes of symptomatic infection in women in whom UTIs are temporally related to intercourse. Other patients for whom prophylaxis appears to have some merit include men with chronic prostatitis; patients undergoing prostatectomy, both during the operation and in the postoperative period; and pregnant women with asymptomatic bacteriuria. All pregnant women should be screened for bacteriuria in the first trimester and should be treated if bacteriuria is demonstrated.

PAPILLARY NECROSIS

When infection of the renal pyramids develops in association with vascular diseases of the kidney or with urinary tract obstruction, renal papillary necrosis is likely to result. Patients with diabetes, sickle cell disease, chronic alcoholism, and vascular disease seem peculiarly susceptible to this complication. Hematuria, pain in the flank or abdomen, and chills and fever are the most common presenting symptoms. Acute renal failure with oliguria or anuria sometimes develops. Rarely, sloughing of a pyramid may take place without symptoms in a patient with chronic UTI1, and the diagnosis is made when the necrotic tissue is passed in the urine or identified as a "ring shadow" on pyelography. If renal function deteriorates suddenly in a diabetic individual or a patient with chronic obstruction, the diagnosis of renal papillary necrosis should be entertained, even in the absence of fever or pain. Renal papillary necrosis is often bilateral; when it is unilateral, however, nephrectomy may be a life-saving approach to the management of overwhelming infection.

EMPHYSEMATOUS PYELONEPHRITIS AND CYSTITIS

These unusual clinical entities almost always occur in diabetic patients, often in concert with urinary obstruction and chronic infection. Emphysematous pyelonephritis is usually characterized by a rapidly progressive clinical course, with high fever, leukocytosis, renal parenchymal necrosis, and accumulation of fermentative gases in the kidney and perinephric tissues. Most patients also have pyuria and glucosuria. E. coli causes most cases, but occasionally other Enterobacteriaceae are isolated. Gas in tissues can often be seen on plain films and can best be confirmed and localized by computed tomography. Surgical resection of the involved tissue in addition to systemic antimicrobial therapy is usually needed to prevent a fatal outcome in emphysematous pyelonephritis.

Emphysematous cystitis also occurs primarily in diabetic patients, usually in association with E. coli or other facultative gram-negative rods and often in relation to bladder outlet obstruction. Patients with this condition are generally less severely ill and have less rapidly progressive disease than those with emphysematous pyelonephritis. The patient typically reports abdominal pain, dysuria, frequency, and (in some cases) pneumaturia. Computed tomography shows gas within both the bladder lumen and the bladder wall. Generally, conservative therapy with systemic antimicrobial agents and relief of outlet obstruction are effective, but some patients do not respond to these measures and require cystectomy.

RENAL AND PERINEPHRIC ABSCESS

Perinephric and Renal Abscesses Perinephric and renal abscesses are not common: The former accounted for only ~0.02% of hospital admissions and the latter for ~0.2% in Altemeier's series of 540 intraabdominal abscesses. While liver abscesses generally arise from contiguous foci of infection or track from other intraabdominal sources and splenic abscesses usually arise from hematogenous spread (e.g., spread from bacterial endocarditis), perinephric and renal abscesses have a different pathogenesis. Before antibiotics became available, most renal and perinephric abscesses were hematogenous in origin, with S. aureus most commonly recovered. Now, in contrast, 75% of perinephric and renal abscesses arise from an initial urinary tract infection. Infection ascends from the bladder to the kidney, with pyelonephritis occurring first. Bacteria may directly invade the renal parenchyma from medulla to cortex. Local vascular channels within the kidney may also facilitate the transport of organisms. Areas of abscess developing within the parenchyma may rupture into the perinephric space. The kidneys and adrenal glands are surrounded by a layer of perirenal fat that, in turn, is surrounded by Gerota's fascia, which extends superiorly to the diaphragm and inferiorly to the pelvic fat. When abscesses extend into the perinephric space, tracking may occur through Gerota's fascia into the psoas or transversalis muscles, into the anterior peritoneal cavity, superiorly to the subdiaphragmatic space, or inferiorly to the pelvis. Of the several risk factors that have been associated with the development of perinephric abscesses, the most important is the presence of concomitant nephrolithiasis producing local obstruction to urinary flow. Of patients with perinephric abscess, 20 to 60% have renal stones. In addition, other structural abnormalities of the urinary tract, a history of urologic surgery, trauma, and diabetes mellitus have all been identified as risk factors.

The organisms most frequently encountered in perinephric and renal abscesses are E. coli, Proteus species, and Klebsiella species. E. coli, the aerobic species most commonly found in the colonic flora, seems to have unique virulence properties in the urinary tract, including factors promoting adherence to uroepithelial cells. The urease of Proteus species splits urea, thereby creating a more alkaline and more hospitable environment for bacterial proliferation. Proteus species are frequently found in association with large struvite stones caused by the precipitation of magnesium ammonium sulfate in an alkaline environment. These stones serve as a nidus for recurrent urinary tract infection. While a single bacterial species is usually recovered from a perinephric or renal abscess, multiple species may also be found. If a urine culture is not contaminated with periurethral flora and is found to contain more than one organism, a perinephric abscess or renal abscess should be considered in the differential diagnosis. Urine cultures may also be polymicrobial in cases of bladder diverticulum.

Candida species should be considered in the etiology of renal abscesses. This fungus may spread to the kidney via the hematogenous route or by ascension from the bladder. The hallmark of the latter route of infection is ureteral obstruction with large fungal balls.

The presentation of perinephric and renal abscesses is quite nonspecific. Flank pain and abdominal pain are common. At least 50% of patients are febrile. Pain may be referred to the groin or leg, particularly with extension of infection. The diagnosis of perinephric abscess, like that of splenic abscess, is frequently delayed, and the mortality rate in some series is appreciable, although lower than in the past. Perinephric or renal abscess should be most seriously considered when a patient presents with symptoms and signs of pyelonephritis and remains febrile after 4 or 5 days, by which time the fever should have resolved. Moreover, when a urine culture yields a polymicrobial flora, when a patient is known to have renal stone disease, or when fever and pyuria coexist with a sterile urine culture, the diagnosis of perinephric or renal abscess should be entertained.

Renal ultrasonography and abdominal CT17 are the most useful diagnostic modalities. If a renal abscess or perinephric abscess is diagnosed, nephrolithiasis should be excluded, especially when a high urinary pH suggests the presence of a urea-splitting organism.

TREATMENT

Treatment for perinephric or renal abscesses, like that for other intraabdominal abscesses, includes drainage of pus and antibiotic therapy directed at the organism(s) recovered. For perinephric abscesses, percutaneous drainage is usually successful.

PROSTATITIS

The term prostatitis has been used for various inflammatory conditions affecting the prostate, including acute and chronic infections with specific bacteria and, more commonly, instances in which signs and symptoms of prostatic inflammation are present but no specific organisms can be detected. Patients with acute bacterial prostatitis can usually be readily identified on the basis of typical symptoms and signs, pyuria, and bacteriuria. To classify a patient with suspected chronic prostatitis correctly, first-void and midstream urine specimens, a prostatic expressate, and a postmassage urine specimen should be quantitatively cultured and evaluated for numbers of leukocytes. On the basis of the results of these studies and other considerations, a panel of the National Institutes of Health has recommended that patients with suspected chronic prostatitis be categorized as having chronic bacterial prostatitis, chronic pelvic pain syndrome, or asymptomatic inflammatory prostatitis. Each of these groups is discussed below.

ACUTE BACTERIAL PROSTATITIS

When it occurs spontaneously, this disease generally affects young men; however, it may also be associated with an indwelling urethral catheter in older men. It is characterized by fever, chills, dysuria, and a tense or boggy, extremely tender prostate. Although prostatic massage usually produces purulent secretions with a large number of bacteria on culture, bacteremia may result from manipulation of the inflamed gland. For this reason and because the etiologic agent can usually be identified by Gram's staining and culture of urine, vigorous prostatic massage should be avoided. In non-catheter-associated cases, the infection is generally due to common gram-negative urinary tract pathogens (E. coli or Klebsiella). Initially, an intravenous fluoroquinolone, third-generation cephalosporin, or aminoglycoside can be administered. The response to antibiotics in acute bacterial prostatitis is usually prompt, perhaps because drugs penetrate more readily into the acutely inflamed prostate. In catheter-associated cases, the spectrum of etiologic agents is broader, including hospital-acquired gram-negative rods and enterococci. The urinary Gram stain may be particularly helpful in such cases. Imipenem, an aminoglycoside, a fluoroquinolone, or a third-generation cephalosporin should be used for initial therapy until the organism has been isolated and its susceptibilities have been determined. The long-term prognosis is good, although in some instances acute infection may result in abscess formation, epididymoorchitis, seminal vesiculitis, septicemia, and residual chronic bacterial prostatitis. Since the advent of antibiotics, the frequency of acute bacterial prostatitis has diminished markedly.

CHRONIC BACTERIAL PROSTATITIS

This entity is now infrequent but should be considered in men with a history of recurrent bacteriuria. Symptoms are often lacking between episodes, and the prostate usually feels normal on palpation. Obstructive symptoms or perineal pain develops in some patients. Intermittently, infection spreads to the bladder, producing frequency, urgency, and dysuria. A pattern of relapsing infection in a middle-aged man strongly suggests chronic bacterial prostatitis. Classically, the diagnosis is established by culture of E. coli, Klebsiella, Proteus, or other uropathogenic bacteria from the expressed prostatic secretion or postmassage urine in higher quantities than are found in first-void or midstream urine. Antibiotics promptly relieve the symptoms associated with acute exacerbations but have been less effective in eradicating the focus of chronic infection in the prostate. The relative ineffectiveness of antimicrobial agents in achieving long-term cure has in part been due to the poor penetration into the prostate by most of these drugs. Fluoroquinolones have been considerably more successful than other antimicrobials, but even they must generally be given for at least 12 weeks to be effective. Patients with frequent episodes of acute cystitis in whom attempts at curative therapy fail can be managed with prolonged courses of low-dose antimicrobial agents (usually a sulfonamide, TMP7, or nitrofurantoin), with a view toward suppressing symptoms and keeping the bladder urine sterile. Total prostatectomy obviously results in the cure of chronic prostatitis but is associated with considerable morbidity. Transurethral prostatectomy is safer but cures only one-third of patients.

CHRONIC PELVIC PAIN SYNDROME (FORMERLY NONBACTERIAL PROSTATITIS)

Patients who present with symptoms of prostatitis (intermittent perineal and low-back pain, obstructive voiding symptoms), few signs on examination, no bacterial growth in cultures, and no history of recurrent episodes of bacterial prostatitis are classified as having chronic pelvic pain syndrome (CPPS). Patients with CPPS are divided into inflammatory and noninflammatory subgroups based on the presence or absence of prostatic inflammation. Prostatic inflammation can be considered present when the expressed prostatic secretion and postmassage urine contain at least tenfold more leukocytes than the first-void and midstream urine specimens or when the expressed prostatic secretion contains =1000 leukocytes per microliter.

The likely etiology of CPPS8 associated with inflammation would be an infectious agent, but the agent has not yet been identified. Evidence for a causative role of both U. urealyticum and C. trachomatis has been presented but is not conclusive. Since most cases of inflammatory CPPS occur in young, sexually active men and since many cases follow an episode of nonspecific urethritis, the causative agent may well be sexually transmitted. The effectiveness of antimicrobial agents in this condition remains uncertain. Some patients benefit from a 4- to 6-week course of treatment with erythromycin, doxycycline, TMP-SMX9, or a fluoroquinolone, but controlled trials are lacking. Patients who have symptoms and signs of prostatitis but who have no evidence of prostatic inflammation (normal leukocyte counts) and negative urine cultures are classified as having noninflammatory CPPS. Despite their symptoms, these patients most likely do not have prostatic infection and should not be given antimicrobial agents.


	6. tubular disorders

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TUBULAR DISORDERS - John R. Asplin, Fredric L. Coe

INTRODUCTION

The renal tubular disorders and their morphologic and functional abnormalities, mode of inheritance, and associated abnormalities are summarized in Table 265-1. The individual disorders are discussed in detail below.

AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Etiology and Pathology Autosomal dominant polycystic kidney disease (ADPKD) has a prevalence of 1:300 to 1:1000 and accounts for ~4% of end-stage renal disease (ESRD) in the United States. Some 90% of cases are inherited as an autosomal dominant trait, and ~10% are spontaneous mutations.

GENETIC CONSIDERATIONS

Three forms of ADPKD1 have been identified. ADPKD-1 accounts for 85% of cases, and the gene has been mapped to chromosome 16p13.3. The gene for ADPKD-2 has been mapped to chromosome 4q21-23. The protein products of the two genes form the polycystin complex, which may regulate cell-cell or cell-matrix interactions. A defect in either of these proteins interrupts the normal function of the polycystin complex, resulting in the same phenotype for two distinct genetic abnormalities. ADPKD-2 appears to have a later age of onset of symptoms and renal failure than ADPKD-1. A rare third form has been described but has not been mapped to a gene at this point.

The kidneys are grossly enlarged, with multiple cysts studding the surface of the kidney. The cysts contain straw-colored fluid that may become hemorrhagic. The cysts are spherical, vary in size from a few millimeters to centimeters, and are distributed evenly throughout the cortex and medulla. Only 1 to 5% of nephrons will develop cysts. Cysts form when a "second hit" causes a somatic mutation in the normal allele of a tubule cell, leading to monoclonal proliferation of the tubular epithelium. The remaining renal parenchyma reveals varying degrees of tubular atrophy, interstitial fibrosis, and nephrosclerosis.

Clinical Features The disease may present at any age but most frequently causes symptoms in the third or fourth decade. Patients may develop chronic flank pain from the mass effect of the enlarged kidneys. Acute pain indicates infection, urinary tract obstruction by clot or stone, or sudden hemorrhage into a cyst. Gross and microscopic hematuria are common, and impaired renal concentrating ability frequently leads to nocturia. Nephrolithiasis occurs in 15 to 20% of patients, calcium oxalate and uric acid stones being most common. Low urine pH, low urine citrate, and urinary stasis from distortion of the collecting system by cysts all play a role in stone formation. Hypertension is found in 20 to 30% of children and up to 75% of adults. It is secondary to intrarenal ischemia from distortion of the renal architecture, leading to activation of the renin-angiotensin system. Patients with hypertension have a much more rapid progression to ESRD2. Urinary tract infection is common and may involve the bladder or renal interstitium (pyelonephritis) or infect a cyst (pyocyst). Pyocysts can be difficult to diagnose but are more likely to be present if the patient has positive blood cultures, new renal pain, or failed to improve clinically after a standard course of antibiotic therapy.

Progressive decline in renal function is common, with ~50% of patients developing ESRD2 by age 60. However, there is considerable variation in age of onset of renal failure, even within the same family. Hypertension, recurrent infections, male sex, and early age of diagnosis are related to early onset renal failure. Renal failure usually progresses slowly; if a sudden decrement in kidney function occurs, ureteral obstruction from stone, clot, or compression by a cyst are likely causes. Patients usually have high hematocrits for their level of renal function, as erythropoietin production is high. Fluid overload is uncommon because of a tendency for renal salt wasting.

Extrarenal manifestations of this disease are frequent and underscore the systemic nature of the defect. Hepatic cysts occur in 50 to 70% of patients. Cysts are generally asymptomatic, and liver function is normal, though women may develop massive hepatic cystic disease on occasion. Cyst formation has also been observed in the spleen, pancreas, and ovaries. Intracranial aneurysms are present in 5 to 10% of asymptomatic patients, with potential for permanent neurologic injury or death from subarachnoid hemorrhage. Screening of all ADPKD1 patients for aneurysms is not recommended, but patients with a family history of subarachnoid hemorrhage should be studied noninvasively with magnetic resonance imaging angiography. Colonic diverticular disease is common, and patients are more likely to develop perforation than the general population with colonic diverticula. Mitral valve prolapse is found in 25% of patients, and the prevalence of aortic and tricuspid valve insufficiency is increased.

Diagnosis Ultrasound is the preferred technique for diagnosis of symptomatic patients and for screening asymptomatic family members. The ability to detect cysts increases with the subject's age: 80 to 90% of ADPKD1 patients over the age of 20 will have detectable cysts, and almost 100% over the age of 30 will have cysts. At least three to five cysts in each kidney is the standard diagnostic criteria for ADPKD. Computed tomography (CT) scan may be more sensitive than ultrasound in detection of small cysts. Genetic linkage analysis is now available for diagnosis of ADPKD but is reserved for cases where radiographic imaging is negative and the need for definitive diagnosis critical, such as screening family members for potential kidney donation.

TREATMENT

The goals of treatment are to slow the rate of progression of renal disease and minimize symptoms. Hypertension and renal infection should be treated aggressively to maintain renal function. Converting enzyme inhibitors are effective antihypertensive agents, though patients should be closely monitored as some develop renal insufficiency and hyperkalemia. Urinary infection is treated in a standard manner unless a pyocyst is suspected, in which case antibiotics that penetrate cysts should be used, such as trimethoprim-sulfamethoxazole, ciprofloxacin, and chloramphenicol. Chronic pain from cysts can be managed by cyst puncture and sclerosis with ethanol.

AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE

GENETIC CONSIDERATIONS

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disease with an incidence of 1:20,000 births. The gene for ARPKD has been localized to chromosome 6p21 and encodes a large novel protein whose function has not yet been determined. In the past, ARPKD was categorized as being of neonatal, infantile, or juvenile form depending on the age of onset and the relative degree of involvement of the kidneys and liver. However, variable clinical presentations within siblings in the same family, as well as the localization of the disease to chromosome 6 in multiple families, support the premise that this is a single genetic disease with variable phenotypic presentation.

At birth the kidneys are enlarged with a smooth external surface. The distal tubules and collecting ducts are dilated into elongated cysts that are arranged in a radial fashion. As the patient ages, the cysts may become more spherical and the disease can be confused with ADPKD1. Interstitial fibrosis is also seen as renal function deteriorates. Liver involvement includes proliferation and dilation of intrahepatic bile ducts as well as periportal fibrosis.

Clinical Features The majority of cases are diagnosed in the first year of life, presenting as bilateral abdominal masses. Death in the neonatal period is most commonly due to pulmonary hypoplasia. Hypertension and impaired urinary concentrating ability are common. The time course to ESRD2 is variable, though many children maintain adequate kidney function for years. Older children present with complications secondary to congenital hepatic fibrosis and generally have less severe kidney disease. Hepatosplenomegaly, portal hypertension, and esophageal varices are frequent complications of ARPKD3.

Diagnosis Ultrasound is the most common technique used to diagnose ARPKD4, prenatally and in childhood. Ultrasound examination reveals enlarged kidneys with increased echogenicity. At times spherical cysts may be seen, potentially leading to an incorrect diagnosis of ADPKD1. A thorough family history and imaging the kidneys of the parents aids in differentiation from other cystic diseases. Hepatic fibrosis seen on imaging studies in association with cystic kidneys supports the diagnosis of ARPKD.

TREATMENT

Aggressive treatment of hypertension and urinary tract infection are the major goals of therapy in order to maintain native renal function as long as possible. Dialysis and transplant are appropriate when kidney failure occurs. Hepatic fibrosis may lead to life-threatening variceal hemorrhage, requiring sclerotherapy or portosystemic shunts.

TUBEROUS SCLEROSIS

Patients with this multisystem disease most commonly present with skin lesions and benign tumors of the central nervous system (Chap. 358). Renal involvement is common; angiomyolipomas are the most frequent abnormality and are usually bilateral. Renal cysts may be present as well and can give an appearance similar to that of ADPKD1. Histologically, the cysts are unique — the cyst lining cells are large with an eosinophilic staining cytoplasm and may form hyperplastic nodules that can fill the cyst space.

GENETIC CONSIDERATIONS

One-third of cases are inherited as an autosomal dominant trait, the rest are due to sporadic mutations. Mutations of tumor-suppression genes have been identified on chromosomes 9q34 (TSCI) and 16p13 (TSC2). Mutations of TSC2 account for the majority of cases and are more likely to be associated with mental retardation and polycystic kidneys. Tuberous sclerosis may be confused with ADPKD1 if extrarenal manifestations are minimal.

VON HIPPEL-LINDAU DISEASE

This autosomal dominant disease is characterized by hemangioblastomas of the retina and the central nervous system (Chap. 358). Renal cysts occur in the majority of cases and are usually bilateral. The VHL gene, located on chromosome 3p25, is a tumor-suppressor gene that regulates hypoxia-induced transcription factors. It is the same gene that is mutated in sporadic renal cell carcinoma. Renal cell carcinoma may be found in 40 to 70% of patients with von Hippel-Lindau disease and is frequently multifocal. Yearly screening of adults using CT5 scans has been recommended in an attempt to diagnose renal cell cancers at an early stage.

MEDULLARY SPONGE KIDNEY

Etiology and Pathology Medullary sponge kidney (MSK) is a congenital disorder. Although some cases have apparent autosomal dominant inheritance, most are sporadic. It is found in 0.5 to 1% of all intravenous pyelograms. Males and females are affected equally. The pathologic lesion is cystic dilation of the inner medullary and papillary collecting ducts. Bilateral renal involvement is present in 70% of cases, but not all papillae are equally affected. The dilated ducts are lined by cuboidal epithelium with areas of pseudostratified and stratified squamous epithelium. Calculi are frequently found in the dilated collecting ducts.

Clinical Features Patients generally present in the third or fourth decade with kidney stones, infection, or recurrent hematuria. The disease is most commonly diagnosed by intravenous pyelogram, which shows linear striations radiating into the renal papillae or small cystic collections of contrast in the dilated ducts (Fig. 265-1). Approximately 60% of patients with MSK6 have stones, and 12% of all stone formers will have MSK. Hypercalciuria occurs with the same frequency in MSK as it does in random stone formers. Papillary nephrocalcinosis occurs more frequently in patients with MSK than in the random stone former. Proteinuria is minimal, if present at all, and renal function is normally preserved unless there is renal damage from recurrent infection or severe stone disease.

TREATMENT

Asymptomatic patients require no specific therapy except to maintain high fluid intake to reduce the risk of nephrolithiasis. If stones are present, standard laboratory evaluation should be done and metabolic abnormalities treated as in any stone former (Chap. 268). Infection should be treated aggressively, and instrumentation of the urinary tract should be minimized to avoid introducing infection.

NEPHRONOPHTHISIS/MEDULLARY CYSTIC DISEASE

GENETIC CONSIDERATIONS

Nephronophthisis (NPH) and medullary cystic disease (MCD) have similar pathologic findings but differ in inheritance pattern and age of onset. NPH is inherited as an autosomal recessive disease. Three forms have been identified, the most common is juvenile (NPH1), which maps to a gene on chromosome 2q13. The infantile form (NPH2) maps to chromosome 9, and the adolescent form (NPH3) maps to chromosome 3. MCD is an autosomal dominant disease. Two loci have been associated with MCD, one on chromosome 1q21 and the other on 16p12. In both NPH and MCD the kidneys tend to be small, with cysts throughout the medulla; the cortex and papilla rarely have cysts. The cysts originate in the collecting ducts, distal convoluted tubules, and loops of Henle and range in size from 1 to 10 mm. Sclerotic glomeruli, tubule atrophy, and interstitial fibrosis are frequent findings on biopsy.

Clinical Features Patients with NPH7 present during childhood with symptoms of polyuria, growth retardation, anemia, and progressive renal insufficiency. ESRD2 develops at an average age of 2 years in NPH2, 13 years in NPH1, and 19 years in NPH3. NPH accounts for 2 to 10% of renal failure in children. Hepatic fibrosis and cerebellar ataxia have been reported in association with NPH. MCD8 presents in the third or fourth decade, though some cases may be diagnosed in the elderly population. Presenting symptoms in MCD are the same as in NPH except for growth retardation. In addition, MCD does not have extrarenal abnormalities. Severe salt wasting can be seen, though this is usually a transient phase that resolves as the disease progresses to ESRD. Other features of tubule damage are often found, including hyperkalemia and hyperchloremic metabolic acidosis. Proteinuria is mild, and hematuria is rare.

Diagnosis The diagnosis is suggested by a family history of renal disease. The pattern of inheritance and age of onset aid in distinguishing NPH9/MCD8 from other inherited diseases. Radiographic studies show small kidneys, loss of the corticomedullary junction, and multiple cysts in the medulla. CT10 scan is more sensitive than ultrasound in making the diagnosis. The majority of cases of NPH can be diagnosed using molecular genetics techniques. Open renal biopsy, including medullary tissue, may be required for diagnosis in some cases.

TREATMENT

Treatment is mainly supportive, as there is no specific therapy to prevent loss of renal function. Patients with salt wasting require a large oral intake of salt and water to maintain adequate extracellular volume. Alkali replacement and erythropoietin are required for acidosis and anemia, respectively. Renal transplantation has been performed in numerous patients, and the disease does not recur.

LIDDLE'S SYNDROME

Liddle's syndrome is a rare autosomal dominant disorder with a clinical presentation of hyperaldosteronism, consisting of hypertension, hypokalemia, and metabolic alkalosis. However, aldosterone levels are undetectable and renin levels are suppressed. The syndrome is caused by activating mutations in the amiloride-sensitive sodium channel, which leads to increased distal tubule sodium reabsorption and potassium wasting. Potassium-sparing diuretics that block the sodium channel, such as amiloride and triamterene, used in conjunction with a low-sodium diet, are effective in treating the hypertension and electrolyte abnormalities. Spironolactone is ineffective, since the disease is not mediated via the aldosterone receptor.

BARTTER'S SYNDROME

Clinical Features Hypokalemia secondary to renal potassium wasting, metabolic alkalosis, and normal to low blood pressure are the clinical features of Bartter's syndrome. Two variants of Bartter's syndrome have been described. Antenatal Bartter's syndrome (also known as hyperprostaglandin E syndrome) is characterized by polyhydramnios and premature delivery. During infancy, episodes of fever and dehydration are common and can lead to growth retardation. Nephrocalcinosis secondary to hypercalciuria is frequent. Prostaglandin E production is very high. Most cases of classic Bartter's syndrome present during childhood. Symptoms such as weakness and cramps are secondary to the hypokalemia. Polyuria and nocturia are common due to the hypokalemia-induced nephrogenic diabetes insipidus. Nephrocalcinosis is less common than in the antenatal form. Both forms are inherited as autosomal recessive traits. Although rarely required for diagnosis, renal biopsy reveals hyperplasia of the juxtaglomerular apparatus and prominence of medullary interstitial cells, with variable degrees of interstitial fibrosis, though these are not pathognomonic for the syndrome.

GENETIC CONSIDERATIONS

Abnormalities in three renal tubule transport proteins have been shown to cause Bartter's syndrome. Mutations in either the bumetanide-sensitive Na-K-2Cl cotransporter or the apical K+ channel (ROMK) have been described in antenatal Bartter's. Mutations of a basolateral chloride channel (CLC-Kb) are found in patients with classic Bartter's syndrome. All of these mutations lead to a loss of Na+ and Cl- reabsorption in the loop of Henle. The resultant volume depletion activates the renin-angiotensin system. Distal delivery of NaCl and water are high in the presence of high aldosterone, promoting secretion of K+ and H+ ions. Prostaglandin overproduction is mediated by volume depletion, hypokalemia, and high angiotensin II and kallikrein levels. Increased prostaglandin production contributes to the severity of disease by inducing resistance to the pressor effects of angiotensin II and reducing reabsorption in the thick ascending limb of the loop of Henle.

Diagnosis Hypokalemia, metabolic alkalosis, and normal to low blood pressure are the clinical findings characteristic of Bartter's syndrome. The differential diagnosis includes vomiting, surreptitious diuretic abuse, and magnesium deficiency. Chronic vomiting can be diagnosed by a low urine Cl- concentration. Magnesium deficiency causes kaluresis and alkalosis, simulating Bartter's syndrome. Serum and urine magnesium will be low in such cases. Diuretic abuse produces metabolic abnormalities indistinguishable from Bartter's syndrome. Urine should be screened for diuretics multiple times before the diagnosis of Bartter's is made in a patient without a family history of the disorder.

TREATMENT

Dietary intake of sodium and potassium should be liberal. Potassium supplements are usually required. Spironolactone will reduce potassium wasting. Nonsteroidal antiinflammatory drugs (NSAIDs) are useful, particularly in patients with antenatal Bartter's syndrome, since they reduce prostaglandin production. Angiotensin-converting enzyme (ACE) inhibitors may be beneficial in some patients.

GITELMAN'S SYNDROME

Gitelman's syndrome shares many features with Bartter's syndrome including hypokalemia, metabolic alkalosis, salt wasting, elevated renin and aldosterone levels, and normal blood pressure. Clinically it is distinguished from Bartter's by hypomagnesemia and hypocalciuria. Gitelman's syndrome is usually diagnosed during adolescence or adulthood, with weakness, fatigue, muscle cramps, and nocturia being the most common symptoms. The syndrome is inherited as an autosomal recessive trait and is due to mutations in the thiazide-sensitive Na-Cl transporter. The reduced Na+ reabsorption in the distal convoluted tubule leads to volume depletion and hypokalemia. Loss of activity of the thiazide-sensitive transporter increases tubule calcium reabsorption, leading to the classic finding of hypocalciuria in Gitelman's syndrome. Treatment consists of liberal dietary sodium intake, potassium and magnesium supplements, and potassium sparing diuretics. Unlike in Bartter's syndrome, NSAIDs11 and ACE12 inhibitors are not effective.

CONGENITAL NEPHROGENIC DIABETES INSIPIDUS

GENETIC CONSIDERATIONS

This rare genetic disorder is most commonly inherited as an X-linked disease, with full expression in males and variable penetrance in females. Vasopressin acts through two receptors; type 1 receptors are located in the vasculature, while type 2 receptors are found in the collecting ducts of the kidney. In X-linked nephrogenic diabetes insipidus (NDI), only the actions requiring type 2 receptors are abnormal. Mutations of the type 2 vasopressin receptor lead to misfolding and trapping of the receptor in the endoplasmic reticulum, with no receptor present on the cell surface. Less frequently, NDI may be inherited as an autosomal trait, either recessive or dominant, in which mutations in the gene for the water channels in collecting duct cells (aquaporin 2) lead to abnormal cell routing of aquaporin 2.

Clinical Features The clinical presentation is that of persistent polyuria, dehydration, and hypotonic urine in the presence of hypernatremia. Vasopressin levels are appropriately elevated in the hypertonic state, but renal response is lacking. About 90% of cases are diagnosed in the first 2.5 years of life. Recurrent hypernatremia may lead to seizures or mental retardation. Once old enough to satisfy their thirst, children will be clinically stable though in a chronic state of polyuria and polydypsia. Renal function is normal, and radiographic studies of the urinary system reveal dilated ureters and bladder secondary to the chronically high urine flow. Since the most common form of the disease is X-linked, most patients are male. Heterozygous females generally have mild concentrating defects, though a few have phenotypic expression similar to males due to skewed X-chromosome inactivation.

TREATMENT

Treatment is aimed at maintaining adequate hydration. In the infant, low-solute feedings and high water intake are generally adequate. Addition of a thiazide diuretic reduces urine flow by inhibiting sodium reabsorption in the distal convoluted tubule. This lowers free water production and, by causing extracellular volume contraction, increases proximal salt and water reabsorption, reducing delivery to the distal nephron. Amiloride or indomethacin are frequently used to potentiate the effects of thiazide diuretics. Administration of vasopressin and its analogues has no role in the management of this disorder.

RENAL TUBULAR ACIDOSIS

Renal tubular acidosis (RTA) is a disorder of renal acidification out of proportion to the reduction in glomerular filtration rate. RTA is characterized by hyperchloremic metabolic acidosis with a normal serum anion gap [Na+ - (Cl- + HCO3-)]. There are multiple forms of RTA, depending on which aspects of renal acid handling have been affected. Defective bicarbonate reabsorption in the proximal tubule, suppressed renal ammoniagenesis, and inadequate distal tubule proton secretion are the abnormalities that produce RTA. Three major forms of RTA exist (Table 265-2). Types 1 and 2 may be inherited or acquired. Type 4 is usually acquired and is associated with either hypoaldosteronism or tubular hyporesponsiveness to mineralocorticoids. Type 3 is a very rare form of RTA with features of both type 1 and type 2 RTA. It is due to deficiency carbonic anhydrase II, an enzyme present in both the proximal and distal tubules. It is an autosomal recessive disease associated with osteopetrosis and mental retardation.

TYPE 1 (DISTAL) RTA13

In this disorder the distal nephron does not lower urine pH normally, either because the collecting ducts permit excessive back-diffusion of hydrogen ions from lumen to blood or because there is inadequate transport of hydrogen ions. Excretion of titratable acid is low, as inadequate proton secretion prevents titration of urinary buffers such as phosphate. Urine ammonium excretion is inappropriately low for the level of acidosis, as the defect in acidification reduces the ion trapping required for ammonium excretion. Urinary concentration and potassium conservation also tend to be impaired.

Chronic acidosis lowers tubule reabsorption of calcium, causing renal hypercalciuria and mild secondary hyperparathyroidism. Buffering of bone by the daily metabolic acid load contributes to hypercalciuria. Urine citrate excretion is low, as acidosis and hypokalemia stimulate proximal tubule reabsorption of citrate. The hypercalciuria, alkaline urine, and low levels of urine citrate cause calcium phosphate stones and nephrocalcinosis. Growth retardation is common and improves with correction of the acidosis by alkali. In both children and adults, bone diseases may result, in part, from acidosis-induced loss of bone material and inadequate production of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Since the kidney does not conserve potassium or concentrate the urine normally, polyuria and hypokalemia occur. With the stress of an intercurrent illness, acidosis and hypokalemia can be life-threatening.

GENETIC CONSIDERATIONS

Type 1 RTA14 can be familial, with autosomal dominant as the most common mode of inheritance. Autosomal recessive and sporadic cases have been reported. Mutations in the basolateral chloride-bicarbonate exchanger (AE1) of intercalated cells have been identified in the autosomal dominant form. The autosomal recessive form has been associated with mutations in the H+-ATPase in some families. Sensorineural deafness frequently accompanies the H+-ATPase mutation. Other hereditary diseases that cause type 1 RTA include galactosemia, Ehler-Danlos syndrome, Fabry's disease, MSK15, Wilson's disease, and hereditary elliptocytosis. The majority of cases of type 1 RTA are secondary to a systemic disorder such as Sjogren's syndrome, hypergammaglobulinemia, chronic active hepatitis, or lupus.

Diagnosis The diagnosis of type 1 RTA16 is suggested by a normal anion gap metabolic acidosis with a simultaneous urine pH 5.5. Calcium phosphate stones or nephrocalcinosis support the diagnosis, though they are not present in all cases. Bicarbonaturia is not present, which distinguishes this disorder from type 2 RTA. If acidosis is not severe and urine pH is equivocal, an oral ammonium chloride loading test may confirm the diagnosis. As systemic acidosis worsens with ammonium chloride, urine pH does not fall below 5.5 in patients with type I RTA.

Chronic diarrheal states cause normal anion gap acidosis and hypokalemia; urine pH may be 5.5 if ammonium production is very high. The urine anion gap (Na+ + K+ - Cl-) can be used to estimate renal ammonium production and distinguish RTA17 from gastrointestinal bicarbonate loss. Normally the urine anion gap is positive, as unmeasured anions exceed unmeasured cations. If urine ammonium levels are high, urine chloride concentration increases to balance the charge. Unmeasured cation (predominantly ammonium) now exceeds unmeasured anion, and the urine anion gap is negative. During metabolic acidosis, a negative urine anion gap suggests an extrarenal cause of acidosis, whereas a positive urine anion gap suggests RTA. The urine anion gap cannot be used if there are large amounts of unmeasured anions, such as bicarbonate or ketones, in the urine.

TREATMENT

Alkali supplements are the standard therapy. Enough alkali is prescribed to titrate the daily metabolic acid production, usually in the range of 0.5 to 2.0 mmol/kg body weight in four to six divided doses per day. Sodium bicarbonate and Shohl's solution are common treatments. Potassium alkali salts can be used if hypokalemia is a persistent problem. Citrate requires less frequent dosing than bicarbonate salts as it is metabolized to bicarbonate after absorption. The dose of alkali should be raised until acidosis and hypercalciuria are both eliminated. Requirements for alkali may rise during intercurrent illnesses but are 4 mmol/kg body weight per day. The relatives of patients with idiopathic type 1 RTA18 should be screened for this disorder, as timely treatment can prevent growth retardation in children. Incomplete RTA secondary to idiopathic hypercalciuria is best treated using thiazide diuretics in conjunction with potassium citrate (Chap. 268).

TYPE 2 (PROXIMAL) RTA

Type 2 RTA19 usually occurs as part of a generalized disorder of proximal tubule function, presenting as hyperchloremic acidosis with other features of Fanconi syndrome. Bicarbonate reabsorption in the proximal tubule is defective. At normal concentrations of plasma bicarbonate, large amounts of bicarbonate are delivered to the distal tubule, overwhelming the absorptive capacity of the distal tubule and resulting in bicarbonaturia. As plasma bicarbonate levels fall, the lower filtered load of bicarbonate can be reabsorbed by the proximal tubule, resulting in normal distal delivery of bicarbonate. At this point the distal nephron can acidify the urine normally, resulting in normal excretion of daily metabolic acid production, albeit at a low serum bicarbonate level. Hypophosphatemia and low calcitriol levels are common and may lead to rickets or osteomalacia. Hypercalciuria occurs, but stone formation is unusual since urine citrate levels are normal or high because of reduced proximal tubule citrate reabsorption. Type 2 RTA without Fanconi syndrome may be inherited as an autosomal dominant or recessive disorder. Mutations in the Na+-HCO3- cotransporter (NBC-1) have been reported in some families with the autosomal recessive form. Type 2 RTA may be acquired in association with other diseases (see "Fanconi Syndrome," below) or be secondary to drugs that inhibit carbonic anhydrase activity, such as acetazolamide.

Type 2 RTA20 may be distinguished from type 1 RTA by the ability to normally acidify urine during spontaneous or ammonium chloride-induced acidosis. Correction of acidosis with bicarbonate will result in bicarbonaturia in type 2 RTA but not in type 1 RTA. Fractional excretion of bicarbonate is 15% at normal or near-normal serum bicarbonate levels. In distal RTA it is 10%. It is unusual for serum bicarbonate levels to fall below 15 mmol/L in proximal RTA. The urine anion gap will be positive, as ammonium excretion is normal to handle daily acid production but is not elevated as in nonrenal causes of acidosis.

TREATMENT

Children should be treated to prevent growth retardation. Alkali must be given in large amounts daily, 5 to 15 mmol/kg body weight per day, because bicarbonate is rapidly excreted in the urine. A thiazide diuretic can be used in conjunction with a low-salt diet to reduce the amount of bicarbonate required. Potassium requirements increase during alkali therapy due to increased renal loss of potassium from bicarbonaturia.

TYPE 4 RTA

In type 4 RTA21, also called hyperkalemic distal RTA, distal tubule secretion of both potassium and hydrogen ions is abnormal, resulting in hyperchloremic acidosis with hyperkalemia. Type 4 RTA is an acquired disorder; a moderate degree of renal insufficiency is present in the majority of patients. Patients with type 4 RTA can be differentiated from patients with type 1 since they have an acid urine (pH 5.5) during periods of acidosis (Table 265-2) and hyperkalemia. They differ from type 2 patients by having a fractional excretion of bicarbonate 10% and a daily bicarbonate requirement of 1 to 3 mmol/kg body weight per day. Because potassium and hydrogen ion excretion are abnormal, such patients are considered to have generalized distal nephron dysfunction due to either insufficient aldosterone production or intrinsic renal disease causing aldosterone resistance. The resulting hyperkalemia reduces proximal tubule ammonia production, in addition to the inadequate proton secretion, leading to inadequate excretion of the daily metabolic proton load. These patients have an acid urine despite reduced proton secretion because there is inadequate ammonia to buffer protons in the distal tubule. If buffer delivery to the distal nephron is increased, urine pH will rise despite persistent acidosis.

Type 4 RTA22 due to inadequate aldosterone production has multiple etiologies. Hyporeninemic hypoaldosteronism is the most common cause of type 4 RTA and is usually associated with diabetic nephropathy. Plasma levels of renin and aldosterone are subnormal, even during extracellular volume depletion. NSAIDs23, ACE24 inhibitors, trimethoprim, and heparin can reduce aldosterone production and produce a type 4 RTA. Drug-induced type 4 RTA is usually seen in patients with preexisting renal insufficiency. Reduced aldosterone production may be due to adrenal disease, occurring as either an isolated defect or as part of a more generalized adrenal disorder (Chap. 321). Renin levels are normal to high in adrenal disorders.

Patients with tubular resistance to aldosterone present with the same clinical features as those with hyporeninemic hypoaldosteronism. A tubulointerstitial process damages the distal tubule, restricting potassium and hydrogen ion excretion, despite adequate aldosterone levels. Obstructive uropathy and sickle cell disease are the most common causes of acquired tubular resistance to aldosterone. Hyporeninemic hypoaldosteronism can be found in addition to tubular aldosterone resistance in many patients. Potassium-sparing diuretics can cause a type 4 RTA25 by producing an aldosterone resistant state.

TREATMENT

The main goal of therapy is to reduce serum potassium, as acidosis will usually improve once the hyperkalemic block of ammonium production is removed. All patients should be placed on a low-potassium diet. Any drug that suppresses aldosterone production or blocks aldosterone effect should be discontinued. Mineralocorticoid supplementation with fludrocortisone, 0.1 to 0.2 mg/d, will improve hyperkalemia and acidosis; however, the patients who also have a partial tubule resistance to mineralocorticoid will require a higher dose. Mineralocorticoid replacement may not be appropriate for patients with hypertension or a history of heart failure. In such situations, a loop diuretic with a liberal sodium intake can usually promote adequate potassium excretion. Exchange resins will reduce potassium levels but are usually not tolerated well enough to be used for long-term treatment.

PSEUDOHYPOALDOSTERONISM

GENETIC CONSIDERATIONS

Type I pseudohyperaldosteronism is transmitted as either an autosomal dominant or recessive trait. The autosomal dominant form is caused by mutations in the mineralocorticoid receptor gene; the autosomal recessive disease is caused by inactivating mutations in the amiloride-sensitive epithelial sodium channel. The aldosterone resistance leads to hyperkalemia, metabolic acidosis, salt wasting, and volume depletion, which present during childhood. Plasma renin and aldosterone levels are elevated. Treatment includes salt supplements, alkali, and potassium restriction.

Type II pseudohypoaldosteronism (also known as Gordon syndrome) presents as hypertension, hyperkalemia, and metabolic acidosis with normal renal function. The disease is inherited as an autosomal dominant trait and appears to be secondary to overactivity of the thiazide sensitive Na-Cl cotransporter. Two genes have been linked to the disease and both encode WNK kinases that are expressed in the distal tubule. Thiazide diuretics control the hypertension and correct the electrolyte disorders.

VITAMIN D DISORDERS

X-LINKED HYPOPHOSPHATEMIC RICKETS (SEE ALSO CHAP. 331)

This disorder is an X-linked dominant disorder characterized by hypophosphatemia with renal phosphate wasting, rickets, and short stature. Hypophosphatemia is present soon after birth; rachitic bowing of the legs develops when the child begins to walk. Children have growth retardation, which is limited almost entirely to the lower extremities. Dentition is delayed, and skull abnormalities are common. Presentation in adults ranges from disabling bone pain to no active symptoms, but generally some physical sign of childhood disease, such as short stature or bowed legs, is present. Overgrowth of bone at joints or sites of muscle attachment may reduce the mobility of the joint or cause nerve entrapment.

Hypophosphatemia secondary to reduced renal phosphate reabsorption is the hallmark of the disease. Serum calcium levels are usually normal, with low intestinal absorption and renal excretion of calcium. Serum alkaline phosphatase and osteocalcin levels are elevated. Parathyroid hormone levels are normal, as would be expected with normal serum calcium. 1,25(OH)2D3 levels are usually normal, though in the setting of hypophosphatemia 1,25(OH)2D3 levels should be elevated. The disease is caused by inactivating mutations in the PHEX gene, located on chromosome Xp22.1, which codes for a membrane-bound endopeptidase. Circulating humoral factors, phosphatonins, that are normally inactivated by the PHEX endopeptidase accumulate in the serum and reduce proximal tubule phosphate reabsorption and 1,25(OH)2D3 production.

TREATMENT

The goal of therapy is to raise serum phosphorous to normal or near-normal levels to improve bone mineralization. Oral neutral phosphate, 1 to 4 g/d in four to six doses, combined with calcitriol is an effective therapy that improves growth rate, reduces bone pain, and leads to radiographically evident improvement of the bone disease. Patients should be closely monitored during therapy as they may develop nephrocalcinosis and renal insufficiency.

AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS

This disorder usually presents during childhood with low serum phosphate from renal phosphate wasting, rickets, and dental abnormalities. There is significant phenotypic variability with some subjects not presenting until adulthood and other cases spontaneously correcting metabolic abnormalities after puberty. The disorder has been linked to a locus on chromosome 12p13, and mutations have been identified in the gene product, fibroblast growth factor (FGF-23). FGF-23 may act as a phosphatonin and promote renal phosphate wasting.

VITAMIN D-DEPENDENT RICKETS TYPE I

GENETIC CONSIDERATIONS

This is an autosomal recessive disorder in which 1,25(OH)2D3 levels are very low but 25-hydroxyvitamin D levels are normal. The disease is caused by inactivating mutations in the gene encoding the 1a-hydroxylase enzyme, leading to a clinical syndrome of vitamin D deficiency.

Symptoms usually appear before the age of 2, including rickets and growth retardation. Levels of serum calcium and phosphorous are low, but that of alkaline phosphatase is elevated. Intestinal calcium absorption and urinary calcium excretion are low. Parathyroid hormone is elevated in response to the hypocalcemia, resulting in increased urinary phosphate losses.

TREATMENT

Calcitriol (0.5 to 1 ug/d) leads to rapid correction of the biochemical abnormalities and resolution of the bone disease. Calcium and phosphorous supplementation are usually not required.

VITAMIN D-DEPENDENT RICKETS TYPE II (SEE ALSO CHAP. 331)

End-organ resistance to 1,25(OH)2D3 is the pathogenesis of this disorder. Serum calcium and phosphate levels are low, secondary hyperparathyroidism is present, and 1,25(OH)2D3 levels are elevated. Inheritance is usually autosomal recessive, though sporadic cases have been reported. Most patients present during childhood with rickets, though some have a milder form of disease not recognized until adulthood. Alopecia is common and tends to be associated with the more severe childhood form of the disease. Mutations in the vitamin D receptor reduce tissue response to 1,25(OH)2D3. Pharmacologic doses of calcitriol (5 to 30 ug/d) along with mineral supplementation will improve the biochemical disorders and bone disease, though some patients have no response to massive doses of calcitriol.

ONCOGENIC OSTEOMALACIA

This syndrome generally occurs in adults with highly vascular mesenchymal tumors. Patients present with bone pain and muscle weakness. Symptoms may be present for years before the correct diagnosis is made. Over 90% of the tumors are benign, and most are found in the extremities or maxillofacial region. Hypophosphatemia secondary to renal phosphate wasting and low levels of 1,25(OH)2D3 are the major biochemical abnormalities. Serum calcium and parathyroid hormone levels are normal. The tumors produce humoral agents, phosphatonins, that reduce proximal tubule phosphate reabsorption and 1a-hydroxylase activity. FGF26-23 is a fibroblast growth factor that has been identified as a potential phosphatonin. Removal of the tumor leads to rapid resolution of the disease. Octreotide therapy reduces secretion of phosphatonins and improves serum phosphorus in some patients with oncogenic osteomalacia.

DENT'S DISEASE

This disorder presents as hypercalciuria, low-molecular-weight proteinuria, calcium nephrolithiasis, and nephrocalcinosis in male children. Progression to renal failure is common. Phosphaturia, glycosuria, aminoaciduria, and other features of Fanconi's syndrome may be present. Females carrying the gene are asymptomatic except for low-molecular-weight proteinuria. Kidney biopsy reveals tubular atrophy, interstitial fibrosis, and medullary calcifications. The gene has been mapped to the short arm of the X chromosome and encodes a voltage-gated chloride channel (CLC-5). Treatment with thiazide diuretics improves the hypercalciuria, but whether thiazides help preserve renal function is not known.

ISOLATED HYPOURICEMIA (SEE ALSO CHAP. 338)

This disorder is generally inherited as an autosomal recessive trait. Most commonly there is deficient urate reabsorption in the proximal tubule, though some patients have been demonstrated to oversecrete urate. Serum uric acid is usually 120 umol/L (2 mg/dL) and hyperuricosuria is common, possibly due to decreased intestinal urate excretion. Hypouricemia is usually an incidental finding, as patients with this disorder are asymptomatic except for an increased risk of nephrolithiasis. Other disorders associated with hypouricemia include Fanconi syndrome, Wilson's disease, Hodgkin's disease, and Hartnup disease. No treatment is required except for high fluid intake to prevent kidney stones. Alkali and allopurinol may be used to prevent stones if fluids alone are not sufficient.

SELECTED DISORDERS OF AMINO ACID TRANSPORT

HARTNUP DISEASE

This disorder is characterized by reduced intestinal absorption and renal reabsorption of neutral amino acids. The defect involves an amino acid transporter on the brush border of the jejunum and the proximal tubule. Intestinal absorption of free amino acids is reduced, though the neutral amino acids can be absorbed when present in di- and tripeptides. Degradation of unabsorbed tryptophan by intestinal bacteria produces indolic acids that are absorbed and subsequently excreted at high levels in the urine of these patients. The disorder is inherited as an autosomal recessive trait with an estimated incidence of 1 in 24,000 live births. Linkage analysis suggests a locus on chromosome 5.

The majority of individuals with this disorder are asymptomatic. Approximately 10 to 20% present with clinical symptoms similar to those seen in pellagra, including a photosensitive erythematous scaly rash, intermittent cerebral ataxia, delirium, and diarrhea. Short stature is noted in some patients. The symptoms are thought to be due to deficiency in the essential amino acid tryptophan and resultant inadequate synthesis of nicotinamide. Though the inheritance of the disorder is autosomal recessive, the development of symptomatic disease appears to be multifactorial. Diet, environment, and polygenic traits controlling plasma amino acid levels all contribute to development of symptoms.

Clinically affected patients can be differentiated from patients with pellagra by dietary history and the presence of aminoaciduria. Diagnosis is made by the characteristic finding of large amounts of neutral amino acids in the urine. It can easily be distinguished from generalized aminoaciduria by the normal excretion of proline. There are no other renal tubule defects as in Fanconi syndrome. Heterozygotes have normal urinary amino acid excretion.

TREATMENT

Symptomatic individuals should receive oral nicotinamide, 40 to 200 mg/d, and a high-protein diet to compensate for the poor amino acid absorption. Some patients who do not respond to nicotinamide may improve with tryptophan ethyl ester, which is lipid soluble and can be absorbed without an active transport system.

FANCONI SYNDROME

GENETIC CONSIDERATIONS

Fanconi syndrome is a generalized defect in proximal tubule transport involving amino acids, glucose, phosphate, uric acid, sodium, potassium, bicarbonate, and proteins. Idiopathic Fanconi syndrome may be inherited as an autosomal dominant, autosomal recessive, or X-linked trait. The autosomal dominant form has been mapped to chromosome 15. Sporadic cases are also seen. A variety of inherited systemic disorders are also associated with Fanconi syndrome including Wilson's disease, galactosemia, tyrosinemia, cystinosis, fructose intolerance, and Lowe's oculocerebral syndrome. The syndrome may be acquired in multiple myeloma, amyloid, heavy metal toxicity, and from chemotherapeutic drugs.

The patients may present with a wide array of laboratory abnormalities including proximal renal tubular acidosis, glucosuria with a normal serum glucose, hypophosphatemia, hypouricemia, hypokalemia, generalized aminoaciduria, and low-molecular-weight proteinuria. Some patients do not have abnormalities in all proximal tubule transporters and may present with only a few of the laboratory findings. Rickets and osteomalacia are common findings secondary to the hypophosphatemia; production of calcitriol may also be abnormal. Metabolic acidosis also contributes to the bone disease. Polyuria, salt wasting, and hypokalemia may be quite severe.

TREATMENT

Treatment includes phosphate supplements and calcitriol to heal the bone lesions, alkali for the acidosis, and liberal intake of salt and water. Alkali in the form of potassium salts may be particularly useful in the patient with RTA27 and hypokalemia. Aminoaciduria, glucosuria, hypouricemia, and low-molecular-weight proteinuria do not require treatment.


	7. vascular injuries

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VASCULAR INJURY TO THE KIDNEY - Kamal F. Badr, Barry M. Brenner

INTRODUCTION

Adequate delivery of blood to the glomerular capillary network is crucial for glomerular filtration and overall salt and water balance. Thus, in addition to the threat to the viability of renal tissue, vascular injury to the kidney may compromise the maintenance of body fluid volume and composition. Involvement of the renal vessels by atherosclerotic, hypertensive, embolic, inflammatory, and hematologic disorders is usually a manifestation of generalized vascular pathology. The morphologic and clinical responses to these insults are considered in this chapter.

THROMBOEMBOLIC DISEASES OF THE RENAL ARTERIES

Thrombosis of the major renal arteries or their branches is an important cause of deterioration of renal function, especially in the elderly. It is often difficult to diagnose and therefore requires a high index of suspicion. Thrombosis may occur as a result of intrinsic pathology in the renal vessels (posttraumatic, atherosclerotic, or inflammatory) or as a result of emboli originating in distant vessels, most commonly fat emboli, emboli originating in the left heart (mural thrombi following myocardial infarction, bacterial endocarditis, or aseptic vegetations), or "paradoxical" emboli passing from the right side of the circulation via a patent foramen ovale or atrial septal defect. Renal emboli are bilateral in 15 to 30% of cases.

The clinical presentation is variable, depending on the time course and the extent of the occlusive event. Acute thrombosis and infarction, such as follows embolization, may result in sudden onset of flank pain and tenderness, fever, hematuria, leukocytosis, nausea, and vomiting. If infarction occurs, renal enzymes may be elevated, namely aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase, which rise and fall in the order listed. Urinary LDH and alkaline phosphatase may also increase after infarction. Renal function deteriorates acutely, leading in bilateral thrombosis to acute oliguric renal failure. More gradual (i.e., atherosclerotic) occlusion of a single renal artery may go undetected. A spectrum of clinical presentations lies between these two extremes. Hypertension usually follows renal infarction and results from renin release in the peri-infarction zone. Hypertension is usually transient but may be persistent. Diagnosis is established by renal arteriography.

TREATMENT

Management of acute renal arterial thrombosis includes surgical intervention, anticoagulant therapy, conservative and supportive therapy, and control of hypertension. The choice of treatment depends mainly on (1) the condition of the patient, in particular the patient's ability to withstand major surgery, and (2) the extent of renovascular occlusion and amount of renal mass at risk of infarction. In general, supportive care and anticoagulant therapy are indicated in unilateral disease. In acute bilateral thrombosis, medical and surgical therapies yield comparable results. Twenty-five percent of patients die during the acute episode, usually from extrarenal complications. In chronic ischemic renal disease, surgical revascularization is more likely to preserve and improve renal function (see below).

ATHEROEMBOLIC DISEASE OF THE RENAL ARTERIES

Atheroembolic renal disease is part of a systemic syndrome characterized by cholesterol crystal embolization. Renal damage results from embolization of cholesterol crystals from atherosclerotic plaques present in large arteries, such as the aorta, to small arteries in the renal vasculature. Atheroembolic renal disease is an increasingly common and often underdiagnosed cause of renal insufficiency in the elderly. A review of 372 autopsies identified cholesterol emboli in 2.4% of renal tissue samples. Male gender, older age, hypertension, and diabetes mellitus are important predisposing factors, present in 85% of cases. Patients with cholesterol embolization syndrome also often have a history of ischemic cardiovascular disease, aortic aneurysm, cerebrovascular disease, congestive heart failure, or renal insufficiency. A significant association is present between renal artery stenosis and atheroembolic renal disease. Inciting events, which include vascular surgery, arteriography, angioplasty, anticoagulation with heparin, and thrombolytic therapy, can be identified in about 50% of cases. Arteriographic procedures constitute the most common cause of cholesterol embolization.

Clinical manifestations usually appear 1 to 14 days after an inciting event, but their onset can be more insidious. Systemic manifestations occur in fewer than half of the patients and include fever, myalgias, headaches, and weight loss. Cutaneous manifestations such as livedo reticularis, "purple" toes, and toe gangrene occur in 50 to 90% of patients and constitute the most common extrarenal findings. Other targets of cholesterol embolization include the retina, musculoskeletal system, nervous system, and gut. Accelerated or labile hypertension is present in one-half of patients. Malignant hypertension has been described. Renal insufficiency is usually subacute and advances in a stepwise fashion over a period of several weeks. Renal failure, however, can be acute and oliguric. Uremic signs and symptoms requiring dialytic therapy develop in 40% of patients, only half of whom recover sufficient renal function to stop dialysis after 1 year. More recent data suggest less inexorable deterioration with a possibility of recovery of renal function in about one-third of patients after variable periods of dialytic support. Renal infarction secondary to cholesterol embolization is rare. Cholesterol embolic disease in renal allografts has been reported and can be of donor or of recipient origin.

Antemortem diagnosis of atherosclerotic renal emboli is difficult. The demonstration of cholesterol emboli in the retina is helpful, but a firm diagnosis is established only by demonstration of cholesterol crystals in the smaller arteries and arterioles on renal biopsy. These may also be seen in asymptomatic skeletal muscle or skin. Atheroembolic renal disease is associated with a 64 to 81% mortality rate.

TREATMENT

No effective therapy for atheroembolic renal disease is available. Withdrawal of anticoagulation may be beneficial. In some patients, kidney function improved even after a prolonged period of renal insufficiency. Cholesterol-lowering agents may also improve outcome. An aggressive therapeutic approach with patient-tailored supportive measures may be associated with more favorable clinical outcome.

RENAL VEIN THROMBOSIS (RVT)

Thrombosis of one or both main renal veins occurs in a variety of settings (Table 267-1). Nephrotic syndrome accompanying membranous glomerulopathy and certain carcinomas seems to predispose to the development of RVT, which occurs in 10 to 50% of patients with these disorders. RVT may exacerbate preexisting proteinuria but is infrequently the cause of the nephrotic syndrome.

The clinical manifestations depend on the severity and abruptness of its occurrence. Acute cases occur typically in children and are characterized by sudden loss of renal function, often accompanied by fever, chills, lumbar tenderness (with kidney enlargement), leukocytosis, and hematuria. Hemorrhagic infarction and renal rupture may lead to hypovolemic shock. In young adults RVT1 is usually suspected from an unexpected and relatively acute or subacute deterioration of renal function and/or exacerbation of proteinuria and hematuria in the appropriate clinical setting. In cases of gradual thrombosis, usually occurring in the elderly, the only manifestation may be recurrent pulmonary emboli or development of hypertension. A Fanconi-like syndrome and proximal renal tubular acidosis have been described.

The definitive diagnosis can only be established through selective renal venography with visualization of the occluding thrombus. Short of angiography, Doppler ultrasound, contrast-enhanced computed tomography (CT), and magnetic resonance imaging (MRI) often provides definitive evidence of thrombus.

TREATMENT

Treatment consists of anticoagulation, the main purpose of which is prevention of pulmonary embolization, although some authors have also claimed improvement in renal function and proteinuria. Encouraging reports have appeared concerning the use of streptokinase. Spontaneous recanalization with clinical improvement has also been observed. Anticoagulant therapy is more rewarding in the acute thrombosis seen in younger individuals. Nephrectomy is advocated in infants with life-threatening renal infarction. Thrombectomy is effective in some cases.

RENAL ARTERY STENOSIS (RAS)/ISCHEMIC RENAL DISEASE

Ischemic renal disease underlies end-stage renal disease in 15 to 20% of uremic patients over 50 years of age. Stenosis of the main renal artery and/or its major branches is causative in 2 to 5% of patients with hypertension (Chap. 230). The common cause in the middle-aged and elderly is an atheromatous plaque at the origin of the renal artery. In a large unselected autopsy series, stenosis producing 50% renal artery diameter reduction was found in 18% of those between 65 and 74 years of age and in 42% of those older than 75 years. Bilateral involvement is present in half of the affected cases in both age groups. It should be considered seriously in elderly individuals, particularly in those with evidence of hypertension, diabetes, and atherosclerotic arterial disease elsewhere. In this population, the incidence of renal arterial stenosis can be as high as 40%. Established plaques progress in 50% of cases over 5 years (15% to total occlusion). Renal hypertrophy is detectable in 20% of affected kidneys. In younger women, stenosis is due to intrinsic structural abnormalities of the arterial wall caused by a heterogeneous group of lesions termed fibromuscular dysplasia. Clinical settings in which RAS should be considered are listed in Table 267-2.

DIAGNOSIS

Diagnostic evaluation for significant RAS2 should begin with noninvasive approaches. An initial screening test is Doppler ultrasonography, which provides information on blood-flow velocity and pressure waveforms in the renal arteries and, when positive, is helpful. Its limitations, however, include significant operator dependence, technical difficulty in obese patients, and poor sensitivity in the presence of multiple renal arteries, distal stenoses, and total occlusion. Measurement of the intrarenal resistance index (RI) by Doppler ultrasonography provides valuable information on the extent of parenchymal tissue loss in stenosed and nonstenosed kidneys and hence on the prognosis for functional recovery following revascularization procedures.

Absence of compensatory hypertrophy in the contralateral kidney should raise the suspicion of bilateral stensosis or superimposed parenchymal renal disease, most commonly hypertensive or diabetic nephropathy. Because angiotensin-converting enzyme (ACE) inhibitors magnify the impairment in renal blood flow and glomerular filtration rate (GFR) caused by functionally significant renal artery stenosis, use of these drugs in association with 99mTc-labeled pentetic acid (DTPA) or 99mTc-labeled mertiatide (MAG3) renography enhances diagnostic precision and is of additional predictive value. Gadolinium-enhanced three-dimensional magnetic resonance angiography (MRA) has replaced previous modalities as the most sensitive (90%) and specific (95%) test for the diagnosis of RAS3. The most definitive diagnostic procedure is contrast-enhanced arteriography. Intraarterial digital subtraction techniques minimize the requirements for contrast, reducing the risk of renal toxicity.

TREATMENT

Interventional therapy RAS4 (i.e., surgery or angioplasty) is superior to medical therapy. Success rates with conventional percutaneous transluminal angioplasty in young patients with fibromuscular dysplasia are 50% cure and improvement in blood pressure control in another 30%. For atherosclerotic lesions, conventional balloon angioplasty is associated with high restenosis rates (up to 47%) and either stent placement or surgery is recommended. About half of those with reduced renal function as a result of RAS improve following angioplasty or surgery, even when preintervention arteriography shows little evidence of cortical perfusion. In the presence of unilateral RAS and normal overall GFR5, the decision for angiographic or surgical revascularization may depend on the results of fractional flow and filtration rate studies to each kidney with 99mTC-DTPA or 99mTc-MAG3. These techniques can also be used to assess the response to revascularization. Three-year survival is influenced by baseline renal function, being 94% in the presence of normal baseline renal function and falling to 52% in patients with serum creatinine 177 umol/L (2.0 mg/dL). Renal parenchymal damage, as reflected in noninvasive imaging and degree of proteinuria, is the major predictor of functional outcome and should be used for risk stratification. Rapid decline in renal function is associated with a favorable response to intervention.

Despite the risks associated with surgery, long-term follow-up studies demonstrate an advantage of surgery over angioplasty both with regard to the incidence of restenosis and to the preservation or improvement in GFR5. Surgery, however, is restricted to those patients in whom angioplasty and stenting are not feasible. As with coronary angioplasty, stenting of renal arteries following balloon angioplasty is being used increasingly. Results are highly encouraging, with restenosis rates 15% at 1 year. Renal functional recovery or stabilization of renal function is seen in approximately 70% of patients. An illustrative example of renal artery stenting is shown in Fig. 267-1.

HEMOLYTIC UREMIC SYNDROME (HUS) AND THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) (SEE ALSO CHAP. 101)

HUS and TTP, consumptive coagulopathies characterized by microangiopathic hemolytic anemia and thrombocytopenia, have a particular predilection for the kidney and the central nervous system, the latter especially in TTP. The kidneys of patients with HUS or TTP often exhibit a "flea-bitten" appearance, the result of multiple cortical hemorrhagic infarcts. The major sites of pathology are the small renal arteries and afferent arterioles, which are nearly occluded as a result of marked intimal hyperplasia (particularly in TTP) and fibrin deposits in the subintimal regions. When the vasoocclusive process is extensive, bilateral cortical necrosis may occur. In addition, arteriolar microaneurysms, glomerular infarction, or nonspecific focal changes may be seen. In keeping with the focal nature of the vascular lesions, patchy areas of interstitial edema, tubular necrosis, and, eventually, fibrosis occur. By immunofluorescence staining, complement components and immunoglobulins may be demonstrated in the arterioles, and fibrinogen deposits are present in arteries, arterioles, and glomerular capillary loops.

Endothelial cell injury appears to be the initiating pathophysiologic event in HUS6/TTP7. Injurious agents include bacterial toxins (Shiga toxin-like) mostly from specific Escherichia coli genotypes, endotoxin (lipopolysaccharides, LPS), bacterial neuraminidases, immune complexes, and drugs. Among the latter, most commonly associated with HUS/TTP are chemotherapeutic agents, cyclosporine, clopidogrel, and quinine. Also implicated in endothelial cell injury are intrinsic abnormalities of the complement sytem and the von Willebrand factor pathways, which may account for the genetic predisposition observed in familial forms of the disease.

Renal failure is common in both HUS8 and TTP9, usually manifested by azotemia, mild proteinuria, and microscopic and/or gross hematuria. Patients with HUS have more severe renal failure, often marked by oligoanuria and hypertension and commonly progressing to chronic renal failure. The prognosis in HUS is better in children than in adults. In TTP, the course of which may span days to months, renal failure is usually less severe.

TREATMENT

In TTP10, high-dose glucocorticoids and plasma exchange often provide complete remission or cure. Plasma exchange should be initiated as early as possible, and the treatment cycles can be repeated if thrombocytopenia recurs. Splenectomy and antiplatelet therapy have also been used with varying degrees of success. The success of plasma exchange in adult HUS11 is less well established than in TTP.

ARTERIOLAR NEPHROSCLEROSIS (SEE ALSO CHAPS. 224 AND 230)

Whether hypertension is "essential" or of known etiology, persistent exposure of the renal circulation to elevated intraluminal pressures results in development of intrinsic lesions of the renal arterioles (hyaline arteriolosclerosis) that eventually lead to loss of function (nephrosclerosis). Nephrosclerosis is divided into two distinct entities: "benign" and "malignant" (or accelerated).

BENIGN ARTERIOLAR NEPHROSCLEROSIS

Benign arteriolar nephrosclerosis is seen in patients who are hypertensive for an extended period of time (blood pressure 150/90 mmHg) but whose hypertension has not progressed to a malignant form (described below). Such patients, usually in the older age group, are often discovered to be hypertensive on routine physical examination or as a result of nonspecific symptomatology (e.g., headaches, weakness, palpitations).

Kidney size is normal to reduced, with loss of cortical mass leading to a fine granularity. Although the larger arteries may show atherosclerotic changes, the characteristic pathology is in the afferent arterioles, which have thickened walls due to deposition of homogeneous eosinophilic material (hyaline arteriolosclerosis). Narrowing of vascular lumina results, with consequent ischemic injury to glomeruli and tubules.

Nephrosclerosis accompanying long-standing systemic arterial hypertension is only one manifestation of a generalized process affecting the cardiovascular system. Physical examination, therefore, may reveal changes in retinal vessels (arteriolar narrowing and/or flame-shaped hemorrhages), cardiac hypertrophy, and possibly signs of congestive heart failure. Renal disease may manifest as a mild to moderate elevation of serum creatinine concentration and/or mild proteinuria. In general, clinical evaluation does not reveal significant renal abnormalities. More specialized examination may disclose elevated urinary albumin excretion, tapering and loss of caliber of intrarenal vessels on arteriography, and an exaggerated natriuresis in response to a fluid challenge. Patients with benign nephrosclerosis generally maintain a near-normal GFR5 despite a reduction in renal blood flow.

MALIGNANT ARTERIOLAR NEPHROSCLEROSIS

Patients with long-standing benign hypertension or patients not previously known to be hypertensive may develop malignant hypertension characterized by a sudden (accelerated) elevation of blood pressure (diastolic often 130 mmHg) accompanied by papilledema, central nervous system manifestations, cardiac decompensation, and acute progressive deterioration of renal function. The absence of papilledema does not rule out the diagnosis in a patient with markedly elevated blood pressure and rapidly declining renal function. The kidneys are characterized by a flea-bitten appearance resulting from hemorrhages in surface capillaries. Histologically, two distinct vascular lesions can be seen. The first, affecting arterioles, is fibrinoid necrosis, i.e., infiltration of arteriolar walls with eosinophilic material including fibrin, thickening of vessel walls and, occasionally, an inflammatory infiltrate (necrotizing arteriolitis). The second lesion, involving the interlobular arteries, is a concentric hyperplastic proliferation of the cellular elements of the vascular wall with deposition of collagen to form a hyperplastic arteriolitis (onion-skin lesion). Fibrinoid necrosis occasionally extends into the glomeruli, which may also undergo proliferative changes or total necrosis. Most glomerular and tubular changes are secondary to ischemia and infarction. The sequence of events leading to the development of malignant hypertension is poorly defined. Two pathophysiologic alterations appear central in its initiation and/or perpetuation: (1) increased permeability of vessel walls to invasion by plasma components, particularly fibrin, which activates clotting mechanisms leading to a microangiopathic hemolytic anemia, thus perpetuating the vascular pathology; and (2) activation of the renin-angiotensin-aldosterone system at some point in the disease process, which contributes to the acceleration and maintenance of blood pressure elevation and, in turn, to vascular injury.

Malignant hypertension is most likely to develop in a previously hypertensive individual, usually in the third or fourth decade of life. There is a higher incidence among men, particularly black men. The presenting symptoms are usually neurologic (dizziness, headache, blurring of vision, altered states of consciousness, and focal or generalized seizures). Cardiac decompensation and renal failure appear thereafter. Renal abnormalities include a rapid rise in serum creatinine, hematuria (at times macroscopic), proteinuria, and red and white blood cell casts in the sediment. Nephrotic syndrome may be present. Elevated plasma aldosterone levels cause hypokalemic metabolic alkalosis in the early phase. Uremic acidosis and hyperkalemia eventually obscure these early findings. Hematologic indices of microangiopathic hemolytic anemia (i.e., schistocytes) are often seen.

TREATMENT

Control of hypertension is the principal goal of therapy for both benign and malignant forms. The time of initiation of therapy, its effectiveness, and patient compliance are crucial factors in arresting the progression of benign nephrosclerosis. Untreated, most of these patients succumb to the extrarenal complications of hypertension. In contrast, malignant hypertension is a medical emergency; its natural course includes a death rate of 80 to 90% within 1 year of onset, almost always due to uremia. Supportive measures should be instituted to control the neurologic, cardiac, and other complications of acute renal failure, but the mainstay of therapy is prompt and aggressive reduction of blood pressure, which, if successful, can reverse all complications in the majority of patients. Presently, 5-year survival is 50%, and some patients have evidence of partial reversal of the vascular lesions and a return of renal function to near-normal levels.

SCLERODERMA (PROGRESSIVE SYSTEMIC SCLEROSIS) (SEE ALSO CHAP. 303)

Renal involvement can present in one of two ways, depending on whether malignant hypertension is superimposed on the renal pathology: (1) Persistent urinary abnormalities with or without hypertension tend to follow an indolent course with mild proteinuria, occasional casts, cellular elements in the urinary sediment, and a propensity for development of hypertension. Azotemia is absent initially, but when it develops, dialysis is required within 1 year. (2) Scleroderma renal crisis (SRC) is a rapid deterioration in renal function, usually accompanied by malignant hypertension, oliguria, fluid retention, microangiopathic hemolytic anemia, and central nervous system involvement. It occurs in 5 to 15% of patients, most commonly in the first 5 years following diagnosis, particularly in patients with diffuse cutaneous involvement. SRC may occur in patients with previously undemonstrable or slowly progressive renal disease. Untreated, it leads to chronic renal failure within days to months.

TREATMENT

The prognosis of scleroderma renal disease is generally poor, particularly following the onset of azotemia. Aggressive antihypertensive therapy may be effective in delaying the progression of renal failure. In SRC12, prompt treatment with ACE13 inhibitors may reverse acute renal failure. Recently, a prospective study on short- and long-term outcomes of SRC in patients who received ACE inhibitors showed that 61% of patients had favorable outcomes (no dialysis or temporary dialysis) with a survival rate at 8 years of 80 to 85%, similar to that of patients with diffuse scleroderma who did not have renal crisis. Moreover, more than half of patients with SRC who initially required dialysis and were treated aggressively with ACE inhibitors were able to discontinue dialysis 3 to 18 months later, suggesting that patients should continue to take ACE inhibitors even after beginning dialysis, in hope of discontinuing it. A significant association exists between antecedent high-dose glucocorticoid therapy and the development of SRC.

SICKLE CELL NEPHROPATHY (SEE ALSO CHAP. 91)

Sickle cell disease causes renal complications that arise mainly as a result of sickling of red blood cells in the microvasculature. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors the sickling of red blood cells, with resultant local infarction (papillary necrosis). Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.

In addition to the intrarenal microvascular pathology described above, young patients with sickle cell disease are characterized by renal hyperperfusion, glomerular hypertrophy, and hyperfiltration. Many of these individuals eventually develop a glomerulopathy leading to glomerular proteinuria (present in as many as 30%) and, in some, the nephrotic syndrome. Co-inheritance of microdeletions in the a-globin gene (a thalassemia) appear to protect against the development of nephropathy, associated with lower mean arterial pressure and less proteinuria.

Mild azotemia and hyperuricemia can also develop. Advanced renal failure and uremia occur in 4 to 18% of cases. Pathologic examination reveals the typical lesion of "hyperfiltration nephropathy," namely, focal segmental glomerular sclerosis. This finding has led to the suggestion that anemia-induced hyperfiltration in childhood is the principal cause of the adult glomerulopathy. Nephron loss secondary to ischemic injury also contributes to the development of azotemia in these patients.

In addition to the glomerulopathy described above, renal complications of sickle cell disease include the following: Cortical infarcts can cause loss of function, persistent hematuria, and perinephric hematomas. Papillary infarcts, demonstrated radiographically in 50% of patients with sickle trait, lead to an increased risk of bacterial infection in the scarred renal tissues and functional tubule abnormalities. Painless gross hematuria occurs with a higher frequency in sickle trait than in sickle cell disease and likely results from infarctive episodes in the renal medulla. Functional tubule abnormalities such as nephrogenic diabetes insipidus result from marked reduction in vasa recta blood flow, combined with ischemic tubule injury. This concentrating defect places these patients at increased risk of dehydration and, hence, sickling crises. The concentrating defect also occurs in individuals with sickle trait. Other tubule defects involve potassium and hydrogen ion excretion, occasionally leading to hyperkalemic metabolic acidosis and a defect in uric acid excretion which, combined with increased purine synthesis in the bone marrow, results in hyperuricemia.

Management of sickle nephropathy is not separate from that of overall patient management (Chap. 91). In addition, however, the use of ACE14 inhibitors has been associated with improvement of the hyperfiltration glomerulopathy. Three-year graft and patient survival in renal transplant recipients with sickle nephropathy is diminished as compared to those with other causes of end-stage renal disease.

TOXEMIAS OF PREGNANCY SEE ALSO CHAP. 6

BILATERAL CORTICAL NECROSIS

Acute bilateral cortical necrosis is associated with septic abortions, abruptio placentae, and preeclampsia. Coagulation in cortical vessels and arterioles leads to renal tissue necrosis. Anuria and renal failure ensue and may be irreversible. In other cases, renal function returns partially, but on long-term follow-up most patients slowly progress to uremia.


	8. stones

Disclaimer: Not mine.. no money made.. don't sue me..

NEPHROLITHIASIS - John R. Asplin, Fredric L. Coe, Murray J. Favus

TYPES OF STONES

Calcium salts, uric acid, cystine, and struvite (MgNH4PO4) are the basic constituents of most kidney stones in the western hemisphere. Calcium oxalate and calcium phosphate stones make up 75 to 85% of the total (Table 268-1) and may be admixed in the same stone. Calcium phosphate in stones is usually hydroxyapatite [Ca5(PO4)3OH] or, less commonly, brushite (CaHPO4H2O).

Calcium stones are more common in men; the average age of onset is the third to fourth decade. Approximately 50% of people who form a single calcium stone eventually form another within the next 10 years. The average rate of new stone formation in recurrent stone formers is about one stone every 2 or 3 years. Calcium stone disease is frequently familial. Uric acid stones are radiolucent and are also more common in men. Half of patients with uric acid stones have gout; uric acid lithiasis is usually familial whether or not gout is present. Cystine stones are uncommon; their radiopacity is due to the sulfur content. Cystine crystals appear in the urine as flat, hexagonal plates. Struvite stones are common and potentially dangerous. These stones occur mainly in women or patients who require chronic bladder catheterization and result from urinary tract infection with urease-producing bacteria, usually Proteus species. The stones can grow to a large size and fill the renal pelvis and calyces to produce a "staghorn" appearance. They are radiopaque and have a variable internal density. In urine, struvite crystals are rectangular prisms said to resemble coffin lids.

MANIFESTATIONS OF STONES

As stones grow on the surfaces of the renal papillae or within the collecting system, they need not produce symptoms. Asymptomatic stones may be discovered during the course of radiographic studies undertaken for unrelated reasons. Stones rank, along with benign and malignant neoplasms, and renal cysts, among the common causes of isolated hematuria. Much of the time, however, stones break loose and enter the ureter or occlude the ureteropelvic junction, causing pain and obstruction.

STONE PASSAGE

A stone can traverse the ureter without symptoms, but passage usually produces pain and bleeding. The pain begins gradually, usually in the flank, but increases over the next 20 to 60 min to become so severe that narcotic drugs may be needed for its control. The pain may remain in the flank or spread downward and anteriorly toward the ipsilateral loin, testis, or vulva. Pain that migrates downward indicates that the stone has passed to the lower third of the ureter, but if the pain does not migrate, the position of the stone cannot be predicted. A stone in the portion of the ureter within the bladder wall causes frequency, urgency, and dysuria that may be confused with urinary tract infection. The vast majority of ureteral stones less than 0.5 cm in diameter will pass spontaneously.

It has been standard practice to diagnose acute renal colic by intravenous pyelography; however, helical computed tomography (CT) scan without radiocontrast enhancement is now the preferred procedure. The advantages of CT include detection of uric acid stones in addition to the traditional radiopaque stones, no exposure to the risk of radiocontrast agents, and possible diagnosis of other causes of abdominal pain in a patient suspected of having renal colic from stones. Ultrasound is not as sensitive as CT in detecting renal or ureteral stones.

OTHER SYNDROMES

Staghorn Calculi Struvite, cystine, and uric acid stones often grow too large to enter the ureter. They gradually fill the renal pelvis and may extend outward through the infundibula to the calyces themselves.

Nephrocalcinosis Calcium stones grow on the papillae. Most break loose and cause colic, but they may remain in place so that multiple papillary calcifications are found by x-ray, a condition termed nephrocalcinosis. Papillary nephrocalcinosis is common in hereditary distal renal tubular acidosis (RTA) and in other types of severe hypercalciuria. In medullary sponge kidney disease (Chap. 265), calcification may occur in dilated distal collecting ducts.

Sludge Sufficient uric acid or cystine in the urine may plug both ureters with precipitate. Calcium oxalate crystals do not do this because less than 100 mg oxalate usually is excreted daily in the urine even in severe hyperoxaluric states, compared with 1000 mg uric acid in patients with hyperuricosuria and 400 to 800 mg cystine in patients with cystinuria. Calcium phosphate crystals can render the urine milky but do not plug the urinary tract.

INFECTION

Although urinary tract infection is not a direct consequence of stone disease, it can occur after instrumentation and surgery of the urinary tract, which are frequent in the treatment of stone disease. Stone disease and urinary tract infection can enhance their respective seriousness and interfere with treatment. Obstruction of an infected kidney by a stone may lead to sepsis and extensive damage of renal tissue, since it converts the urinary tract proximal to the obstruction into a closed, or partially closed, space that can become an abscess. Stones may harbor bacteria in the stone matrix, leading to recurrent urinary tract infection. On the other hand, infection due to bacteria that possess the enzyme urease can cause stones composed of struvite.

ACTIVITY OF STONE DISEASE

Active disease means that new stones are forming or that preformed stones are growing. Sequential radiographs of the renal areas are needed to document the growth or appearance of new stones and to ensure that passed stones are actually newly formed, not preexistent ones.

PATHOGENESIS OF STONES

Urinary stones usually arise because of the breakdown of a delicate balance. The kidneys must conserve water, but they must excrete materials that have a low solubility. These two opposing requirements must be balanced during adaptation to diet, climate, and activity. The problem is mitigated to some extent by the fact that urine contains substances that inhibit crystallization of calcium salts and others that bind calcium in soluble complexes. These protective mechanisms areless than perfect. When the urine becomes supersaturated with insoluble materials, because excretion rates are excessive and/or because water conservation is extreme, crystals form and may grow and aggregate to form a stone.

SUPERSATURATION

In a solution in equilibrium with crystals of calcium oxalate, the product of the chemical activities of the calcium and oxalate ions in the solution is termed the equilibrium solubility product. If crystals are removed, and if either calcium or oxalate ions are added to the solution, the activity product increases, but no new crystals form. Such a solution is metastably supersaturated. If new calcium oxalate seed crystals are now added, they will grow in size. Ultimately, as calcium or oxalate are added to the solution, the activity product reaches a critical value at which a solid phase begins to develop spontaneously. This value is called the upper limit of metastability. Stone growth in the urinary tract requires a urine that, on average, is above the equilibrium solubility product. Excessive supersaturation is common in stone formation.

Calcium, oxalate, and phosphate form many stable soluble complexes among themselves and with other substances in urine, such as citrate. As a result, their free ion activities are below their chemical concentrations and can be measured only by indirect techniques. Reduction in ligands such as citrate can increase ion activity, and therefore supersaturation, without changing total urinary calcium. Urine supersaturation can be increased by dehydration or by overexcretion of calcium, oxalate, phosphate, cystine, or uric acid. Urine pH is also important; phosphate and uric acid are weak acids that dissociate readily over the physiologic range of urine pH. Alkaline urine contains more dibasic phosphate, favoring deposits of brushite and apatite. Below a urine pH of 5.5, uric acid crystals (pK 5.47) predominate, whereas phosphate crystals are rare. The solubility of calcium oxalate, on the other hand, is not influenced by changes in urine pH. Measurements of supersaturation in a pooled 24-h urine sample probably underestimate the risk of precipitation. Transient dehydration, variation of urine pH, and postprandial bursts of overexcretion may cause values considerably above average.

NUCLEATION

In urine that is supersaturated with respect to calcium oxalate, these two ions form clusters. Most small clusters eventually disperse because the internal forces that hold them together are too weak to overcome the random tendency of ions to move away. Large ion clusters can remain stable because attractive forces balance surface losses. Once they are stable, nuclei can grow at levels of supersaturation below that needed for their creation. Cell debris, calcifications on the renal papillae, and other urinary crystals can serve as templates for crystal formation, a process known as heterogeneous nucleation. Heterogeneous nucleation lowers the level of supersaturation required for crystal formation and is likely the mechanism by which stones form in human urine.

INHIBITORS OF CRYSTAL FORMATION

Stable nuclei must grow and aggregate to produce a stone of clinical significance. Urine contains potent inhibitors of nucleation, growth, and aggregation for calcium oxalate and calcium phosphate but not for uric acid, cystine, or struvite. Inorganic pyrophosphate is a potent inhibitor that appears to affect calcium phosphate more than calcium oxalate crystals. Citrate inhibits crystal growth and nucleation, though most of the stone inhibitory activity of citrate is due to lowering urine supersaturation via complexation of calcium. Other urine components such as glycoproteins inhibit all three processes of calcium oxalate stone formation. As a consequence of the presence of these inhibitors, crystal growth in urine is slow compared with growth in simple salt solutions, and the upper limit of metastability is higher.

EVALUATION AND TREATMENT OF PATIENTS WITH NEPHROLITHIASIS

Most patients with nephrolithiasis have remediable metabolic disorders that cause stones and can be detected by chemical analyses of serum and urine. Adults with recurrent kidney stones and children with even a single kidney stone should be evaluated. A practical outpatient evaluation consists of two or three 24-h urine collections, with a corresponding blood sample; measurements of serum and urine calcium, uric acid, electrolytes, and creatinine, and urine pH, volume, oxalate, and citrate should be made. Since stone risks vary with diet, activity, and environment, at least one urine collection should be made on a weekend when the patient is at home and another on a work day. When possible, the composition of kidney stones should be determined because treatment depends on stone type (Table 268-1). No matter what disorders are found, every patient should be counseled to avoid dehydration and to drink copious amounts of water. The efficacy of high fluid intake was confirmed in a prospective study of first-time stone formers. Increasing urine volume to 2.5 L per day resulted in a 50% reduction of stone recurrence compared to the control group. Because treatment is prolonged, the use of medications must be justified by the activity and severity of stone disease and the importance of protection against new stones.

TREATMENT

The management of stones already present in the kidneys or urinary tract requires a combined medical and surgical approach. The specific treatment depends on the location of the stone, the extent of obstruction, the function of the affected and unaffected kidney, the presence or absence of urinary tract infection, the progress of stone passage, and the risks of operation or anesthesia given the clinical state of the patient. In general, severe obstruction, infection, intractable pain, and serious bleeding are indications for removal of a stone.

In the past, stones were removed by operation or by passing a flexible basket retrograde up the ureter from the bladder during cystoscopy. There are now three alternatives. Extracorporeal lithotripsy causes the in situ fragmentation of stones in the kidney, renal pelvis, or ureter by exposing them to shock waves. The kidney stone is centered at a focal point of parabolic reflectors, and high-intensity shock waves are created by high-voltage discharge. The waves are transmitted to the patient using water as a conduction medium, either by placing the patient in a water tank or by placing water-filled cushions between the patient and the shock wave generators. After multiple discharges, most stones are reduced to powder that moves through the ureter into the bladder. Percutaneous nephrolithotomy requires the passage of a cystoscope-like instrument into the renal pelvis through a small incision in the flank. Stones are then disrupted by a small ultrasound transducer or holmium laser. The last method is lithotripsy via a ureteroscope for removal of ureteral stones. These various forms of lithotripsy have largely replaced pyelolithotomy and ureterolithotomy.

CALCIUM STONES

Idiopathic Hypercalciuria (See also Chap. 332) This condition appears to be hereditary, and its diagnosis is straightforward (Table 268-1). In some patients, primary intestinal hyperabsorption of calcium causes transient postprandial hypercalcemia that suppresses secretion of parathyroid hormone. The renal tubules are deprived of the normal stimulus to reabsorb calcium at the same time that the filtered load of calcium is increased. In other patients, reabsorption of calcium by the renal tubules appears to be defective, and secondary hyperparathyroidism is evoked by urinary losses of calcium. Renal synthesis of 1,25-dihydroxyvitamin D is increased, enhancing intestinal absorption of calcium. In the past, the separation of "absorptive" and "renal" forms of hypercalciuria was used to guide treatment. However, these may not be distinct entities but the extremes of a continuum of behavior. Vitamin D overactivity, either through high calcitriol levels or excess vitamin D receptor, is a likely explanation for the hypercalciuria in many of these patients. Hypercalciuria contributes to stone formation by raising urine saturation with respect to calcium oxalate and calcium phosphate.

TREATMENT

For many years the standard therapy for hypercalciuria was dietary calcium restriction. However, recent studies have shown that low-calcium diets increase the risk of incident stone formation. In addition, hypercalciuric stone formers have reduced bone mineral density and an increased risk of fracture compared to the non-stone-forming population. Low calcium intake likely contributes to the low bone mineral density. A recent prospective trial compared the efficacy of a low-calcium diet to a low-protein, low-sodium, normal-calcium diet in preventing stone recurrence in male calcium stone formers. The group on the low-calcium diet had a significantly greater rate of stone relapse. As a whole, low-calcium diets do not appear to be efficacious and carry a long-term risk of bone disease in the stone-forming population. Low-sodium and low-protein diets are a superior option in stone formers. If diet therapy is not sufficient to prevent stones, then thiazide diuretics may be used. Thiazide diuretics lower urine calcium and are effective in preventing the formation of stones. Three 3-year randomized trials have shown a 50% decrease in stone formation in the thiazide-treated groups as compared to the placebo-treated controls. The drug effect requires slight contraction of the extracellular fluid volume, and massive use of NaCl reduces its therapeutic effect. Thiazide-induced hypokalemia should be aggressively treated since hypokalemia will reduce urine citrate, increasing urine calcium ion levels.

Hyperuricosuria About 20% of calcium oxalate stone formers are hyperuricosuric, primarily because of an excessive intake of purine from meat, fish, and poultry. The mechanism of stone formation is probably due to salting out calcium oxalate by urate. A low-purine diet is desirable but difficult for many patients to achieve. The alternative is allopurinol, which has been shown to be effective in a randomized, controlled trial. A dose of 100 mg bid is usually sufficient.

Primary Hyperparathyroidism (See also Chap. 332) The diagnosis of this condition is established by documenting that hypercalcemia that cannot be otherwise explained is accompanied by inappropriately elevated serum concentrations of parathyroid hormone. Hypercalciuria, usually present, raises the urine supersaturation of calcium phosphate and/or calcium oxalate (Table 268-1). Prompt diagnosis is important because parathyroidectomy should be carried out before renal damage or bone disease occurs.

Distal Renal Tubular Acidosis (See also Chap. 265) The defect in this condition seems to reside in the distal nephron, which cannot establish a normal pH gradient between urine and blood, leading to hyperchloremic acidosis. The diagnosis is suggested by a minimum urine pH above 5.5 in the presence of systemic acidosis. If the diagnosis is in doubt because metabolic abnormalities are mild, oral challenge with NH4Cl, 1.9 mmol/kg of body weight, will not lower urine pH below 5.5 in patients with distal RTA1. Hypercalciuria, an alkaline urine, and a low urine citrate level cause supersaturation with respect to calcium phosphate. Calcium phosphate stones form, nephrocalcinosis is common, and osteomalacia or rickets may occur. Renal damage is frequent, and glomerular filtration rate falls gradually.

Treatment with supplemental alkali reverses hypercalciuria and limits the production of new stones. The usual dose of sodium bicarbonate is 0.5 to 2.0 mmol/kg of body weight per day in four to six divided doses. An alternative is potassium citrate supplementation, given at the same dose per day but needing to be given only three to four times per day. In incomplete distal RTA1, systemic acidosis is absent, but urine pH cannot be lowered below 5.5 after an exogenous acid load such as ammonium chloride. Incomplete RTA may develop in some patients who form calcium oxalate stones because of idiopathic hypercalciuria; the importance of RTA in producing stones in this situation is uncertain, and thiazide treatment is a reasonable alternative. Some patients with incomplete RTA form calcium phosphate stones because of low urine citrate and an alkaline urine and are best treated with alkali as if RTA were complete. When treating patients with alkali it is prudent to monitor changes in urine citrate and pH. If urine pH increases without an increase in citrate then calcium phosphate supersaturation will increase and stone disease may worsen.

Hyperoxaluria Oxalate is a metabolic end product in humans. Urine oxalate comes from diet and endogenous metabolic production, with approximately 40 to 50% originating from dietary sources. The upper limit of normal for oxalate excretion is generally considered to be 40 to 50 mg per day. Mild hyperoxaluria (50 to 80 mg/d) is usually caused by excessive intake of high-oxalate foods such as spinach, nuts, and chocolate. In addition, low-calcium diets may promote hyperoxaluria as there is less calcium binding oxalate in the intestine, increasing the amount of oxalate available for absorption. Enteric hyperoxaluria is a consequence of small bowel disease resulting in fat malabsorption. Oxalate excretion is often over 100 mg per day. Enteric hyperoxaluria may be caused by jejunoileal bypass for obesity, bacterial overgrowth syndromes, pancreatic insufficiency, or extensive small intestine involvement from Crohn's disease. With fat malabsorption, calcium in the bowel lumen is bound by fatty acids instead of oxalate, which is left free for absorption in the colon. Delivery of unabsorbed fatty acids and bile salts to the colon may injure the colonic mucosa and enhance oxalate absorption. Hereditary hyperoxaluria states are rare causes of severe hyperoxaluria, often greater than 150 mg per day. Patients usually present with recurrent calcium oxalate stones during childhood. Type I hereditary hyperoxaluria is inherited as an autosomal recessive trait and is due to a deficiency in the peroxisomal enzyme alanine:glyoxylate aminotransferase. Type II is due to a deficiency of D-glyceric dehydrogenase. Severe hyperoxaluria from any cause can produce tubulointerstitial nephropathy (Chap. 266) and lead to stone formation.

TREATMENT

Patients with mild to moderate hyperoxaluria should be treated with a diet low in oxalate and with a normal intake of calcium and magnesium to reduce oxalate absorption. Enteric hyperoxaluria can be treated with the oxalate-binding resin cholestyramine at a dose of 8 to 16 g/d, correction of fat malabsorption, and a low-fat, low-oxalate diet. Calcium supplements, given with meals, precipitate oxalate in the gut lumen, providing an additional form of therapy. Treatment for hereditary hyperoxaluria includes a high fluid intake, neutral phosphate, and pyridoxine (25 to 200 mg/d). Citrate supplementation may also have some benefit. Even with aggressive therapy, irreversible renal failure secondary to recurrent stone formation often occurs. Segmental liver transplant, to correct the enzyme defect, combined with a kidney transplant has been successfully utilized in patients with hereditary hyperoxaluria.

Hypocitraturia Urine citrate prevents calcium stone formation by creating a soluble complex with calcium, effectively reducing free urine calcium. Hypocitraturia is found in 15 to 60% of stone formers, either as a single disorder or in combination with other metabolic abnormalities. It can be secondary to systemic disorders, such as RTA1, chronic diarrheal illness, or hypokalemia, or it may be a primary disorder, in which case it is called idiopathic hypocitraturia.

TREATMENT

Treatment is with alkali, which increases urine citrate excretion; generally bicarbonate or citrate salts are used. Potassium salts are preferred as sodium loading increases urinary excretion of calcium, reducing the effectiveness of treatment. Two randomized, placebo-controlled trials have demonstrated the effectiveness of citrate supplements in calcium oxalate stone formers.

Idiopathic Calcium Lithiasis Some patients have no metabolic cause for stones despite a thorough metabolic evaluation (Table 268-1). The best treatment appears to be high fluid intake so that the urine specific gravity remains at 1.005 or below throughout the day and night. Thiazide diuretics, allopurinol, and citrate therapy may help reduce crystallization of calcium salts, but there are no prospective trials in this patient population. Oral phosphate at a dose of 2 g phosphorus daily may lower urine calcium and increase urine pyrophosphate and thereby reduce the rate of recurrence. Orthophosphate causes mild nausea and diarrhea, but tolerance may improve with continued intake.

URIC ACID STONES

These stones form because the urine becomes supersaturated with undissociated uric acid that is protonated at its N-9 position. In gout, idiopathic uric acid lithiasis, and dehydration, the average pH is usually below 5.4 and often below 5.0. Undissociated uric acid therefore predominates and is soluble in urine only in concentrations of 100 mg/L. Concentrations above this level represent supersaturation that causes crystals and stones to form. Hyperuricosuria, when present, increases supersaturation, but urine of low pH can be supersaturated with undissociated uric acid even though the daily excretion rate is normal. Myeloproliferative syndromes, chemotherapy of malignant tumors, and Lesch-Nyhan syndrome cause such massive production of uric acid and consequent hyperuricosuria that stones and uric acid sludge form even at a normal urine pH. Plugging of the renal collecting tubules by uric acid crystals can cause acute renal failure.

TREATMENT

The two goals of treatment are to raise urine pH and to lower excessive urine uric acid excretion to less than 1 g/d. Supplemental alkali, 1 to 3 mmol/kg of body weight per day, should be given in three or four evenly spaced, divided doses, one of which should be given at bedtime. The form of the alkali may be important. Potassium citrate may reduce the risk of calcium salts crystallizing when urine pH is increased, whereas sodium citrate or sodium bicarbonate may increase the risk. If the overnight urine pH is below 5.5, the evening dose of alkali may be raised or 250 mg acetazolamide added at bedtime. A low-purine diet should be instituted in those uric acid stone formers with hyperuricosuria. Patients who continue to form uric acid stones despite treatment with fluids, alkali, and a low-purine diet should have allopurinol added to their regimen. If hypercalciuria is also present, it should be specifically treated, as alkali alone could lead to calcium phosphate stone formation.

CYSTINURIA AND CYSTINE STONES (SEE ALSO CHAP. 343)

In this autosomal recessive disorder, proximal tubular and jejunal transport of the dibasic amino acids cystine, lysine, arginine, and ornithine are defective, and excessive amounts are lost in the urine. Clinical disease is due solely to the insolubility of cystine, which forms stones.

Pathogenesis Cystinuria occurs because of defective transport of dibasic amino acids by the brush borders of renal tubule and intestinal epithelial cells. The disease classically has been broken into three types based on differences in intestinal and renal amino acid handling in families. However, genomic studies suggest type II and type III cystinuria are due to defects in the same protein. Disease-causing mutations have been identified in both the heavy and light chain of a heteromeric amino acid transporter found in the proximal tubule of the kidney. A gene located on chromosome 2 and designated SLC3A1 encodes the heavy chain of the transporter and has been found to be abnormal in type I cystinuria. Non-type-I cystinuria is due to mutations in the SLC7A9 gene on chromosome 19, which encodes the light chain of the heteromeric transporter.

Diagnosis Cystine stones are formed only by patients with cystinuria, but 10% of stones in cystinuric patients do not contain cystine; therefore, every stone former should be screened for the disease. The sediment from a first morning urine specimen in many patients with homozygous cystinuria reveals typical flat, hexagonal, platelike cystine crystals. Cystinuria also can be detected using the urine sodium nitroprusside test. Because the test is sensitive, it is positive in many asymptomatic heterozygotes for cystinuria. A positive nitroprusside test or the finding of cystine crystals in the urine sediment should be evaluated by measurement of daily cystine excretion. Normal adults excrete 40 to 60 mg cystine per gram of creatinine, heterozygotes usually excrete less than 300 mg/g, and homozygotes almost always excrete greater than 250 mg/g.

TREATMENT

High fluid intake, even at night, is the cornerstone of therapy. Daily urine volume should exceed 3 L. Raising urine pH with alkali is helpful, provided the urine pH exceeds 7.5. A low-salt diet (100 mmol/d) can reduce cystine excretion up to 40%. Because side effects are frequent, drugs such as penicillamine and tiopronin, which form the soluble disulfide cysteine-drug complexes, should be used only when fluid loading, salt reduction, and alkali therapy are ineffective. Captopril, which has a free sulfhydryl group to bind cysteine, has been used in a limited number of patients with some success. Low-methionine diets have not proved to be practical for clinical use, but patients should avoid protein gluttony.

STRUVITE STONES

These stones are a result of urinary infection with bacteria, usually Proteus species, which possess urease, an enzyme that degrades urea to NH3 and CO2. The NH3 hydrolyzes to NH4+ and raises urine pH to 8 or 9. The CO2 hydrates to H2CO3 and then dissociates to CO32- that precipitates with calcium as CaCO3. The NH4+ precipitates PO43- and Mg2+ to form MgNH4PO4 (struvite). The result is a stone of calcium carbonate admixed with struvite. Struvite does not form in urine in the absence of infection, because NH4+ concentration is low in urine that is alkaline in response to physiologic stimuli. Chronic Proteus infection can occur because of impaired urinary drainage, urologic instrumentation or surgery, and especially with chronic antibiotic treatment, which can favor the dominance of Proteus in the urinary tract.

TREATMENT

Complete removal of the stone with subsequent sterilization of the urinary tract is the treatment of choice for patients who can tolerate the procedures. Open surgery is successful in debulking the stone and improving renal function if obstruction is present; however, there is recurrence of stone in 25% of the patients. Irrigation of the renal pelvis and calyces with hemiacidrin, a solution that dissolves struvite, can reduce recurrence after surgery. Newer procedures such as lithotripsy and percutaneous nephrolithotomy, alone or in combination, have largely replaced open surgery. Stone-free rates of 50 to 90% have been reported after these procedures. Antimicrobial treatment is best reserved for dealing with acute infection and for maintenance of a sterile urine after surgery. Urine cultures and culture of stone fragments removed at surgery should guide the choice of antibiotic. For patients who are not candidates for surgical removal of stone, acetohydroxamic acid, an inhibitor of urease, can be used. Though effective in treating the stones, acetohydroxamic acid has many side effects, such as headache, tremor, and thrombophlebitis, that limit its use.


	9. tract obstruction

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URINARY TRACT OBSTRUCTION - Julian L. Seifter, Barry M. Brenner

INTRODUCTION

Obstruction to the flow of urine, with attendant stasis and elevation in urinary tract pressure, impairs renal and urinary conduit functions and is a common cause of acute and chronic renal failure. With early relief of obstruction, the defects in function usually disappear completely. However, chronic obstruction may produce permanent loss of renal mass (renal atrophy) and excretory capability, as well as enhanced susceptibility to local infection and stone formation. Early diagnosis and prompt therapy are therefore essential to minimize the otherwise devastating effects of obstruction on kidney structure and function.

ETIOLOGY

Obstruction to urine flow can result from intrinsic or extrinsic mechanical blockade as well as from functional defects not associated with fixed occlusion of the urinary drainage system. Mechanical obstruction can occur at any level of the urinary tract, from the renal calyces to the external urethral meatus. Normal points of narrowing, such as the ureteropelvic and ureterovesical junctions, bladder neck, and urethral meatus, are common sites of obstruction. When blockage is above the level of the bladder, unilateral dilatation of the ureter (hydroureter) and renal pyelocalyceal system (hydronephrosis) occur; lesions at or below the level of the bladder cause bilateral involvement.

Common forms of obstruction are listed in Table 270-1. Childhood causes include congenital malformations such as narrowing of the ureteropelvic junction and anomalous (retrocaval) location of the ureter. Posterior urethral valves are the most common cause of bilateral hydronephrosis in boys. Bladder dysfunction may be secondary to congenital urethral stricture, urethral meatal stenosis, or bladder neck obstruction. In adults, urinary tract obstruction is due mainly to acquired defects. Pelvic tumors, calculi, and urethral stricture predominate. Ligation of, or injury to, the ureter during pelvic or colonic surgery can lead to hydronephrosis which, if unilateral, may remain relatively silent and undetected. Schistosoma haematobium and genitourinary tuberculosis are infectious causes of ureteral obstruction. Obstructive uropathy may also result from extrinsic neoplastic (carcinoma of cervix or colon) or inflammatory disorders. Retroperitoneal fibrosis, an inflammatory condition in middle-aged men, must be distinguished from other retroperitoneal causes of ureteral obstruction, particularly lymphomas and pelvic neoplasms.

Functional impairment of urine flow usually results from disorders that involve both the ureter and bladder. Causes include neurogenic bladder, often with adynamic ureter, and vesicoureteral reflux. Reflux of urine from bladder to ureter(s) is more common in children, may result in severe unilateral or bilateral hydroureter and hydronephrosis. Abnormal insertion of the ureter into the bladder is the most common cause. Vesicoureteral reflux in the absence of urinary tract infection or bladder neck obstruction usually does not lead to renal parenchymal damage and often resolves with age. Reinsertion of the ureter into the bladder is indicated if reflux is severe and unlikely to improve spontaneously, if renal function deteriorates, or if urinary tract infections recur despite chronic antimicrobial therapy. Hydronephrosis is common in pregnancy, due both to ureteral compression by the enlarged uterus and to functional effects of progesterone.

CLINICAL FEATURES

The pathophysiology and clinical features of urinary tract obstruction are summarized in Table 270-2. Pain, the symptom that most commonly leads to medical attention, is due to distention of the collecting system or renal capsule. Pain severity is influenced more by the rate at which distention develops than by the degree of distention. Acute supravesical obstruction, as from a stone lodged in a ureter (Chap. 268), is associated with excruciatingly severe pain, usually called renal colic. This pain is relatively steady and continuous, with little fluctuation in intensity, and often radiates to the lower abdomen, testes, or labia. By contrast, more insidious causes of obstruction, such as chronic narrowing of the ureteropelvic junction, may produce little or no pain yet result in total destruction of the affected kidney. Flank pain that occurs only with micturition is pathognomonic of vesicoureteral reflux.

Azotemia develops when overall excretory function is impaired, often in the setting of bladder outlet obstruction, bilateral renal pelvic or ureteric obstruction, or unilateral disease in a patient with a solitary functioning kidney. Complete bilateral obstruction should be suspected when acute renal failure is accompanied by anuria. Any patient with renal failure otherwise unexplained, or with a history of nephrolithiasis, hematuria, diabetes mellitus, prostatic enlargement, pelvic surgery, trauma, or tumor should be evaluated for urinary tract obstruction.

In the acute setting, bilateral obstruction may mimic prerenal azotemia. However, with more prolonged obstruction, symptoms of polyuria and nocturia commonly accompany partial urinary tract obstruction and result from impaired renal concentrating ability. This defect usually does not improve with administration of vasopressin and is therefore a form of acquired nephrogenic diabetes insipidus. Disturbances in sodium chloride transport in the ascending limb of Henle and, in azotemic patients, the osmotic (urea) diuresis per nephron lead to decreased medullary hypertonicity and hence a concentrating defect. Partial obstruction, therefore, may be associated with increased rather than decreased urine output. Indeed, wide fluctuations in urine output in a patient with azotemia should always raise the possibility of intermittent or partial urinary tract obstruction. If fluid intake is inadequate, severe dehydration and hypernatremia may develop. Hesitancy and straining to initiate the urinary stream, postvoid dribbling, urinary frequency, and incontinence are common with obstruction at or below the level of the bladder.

Partial bilateral urinary tract obstruction often results in acquired distal renal tubular acidosis, hyperkalemia, and renal salt wasting. These defects in tubule function are often accompanied by renal tubulointerstitial damage. Initially the interstitium becomes edematous and infiltrated with mononuclear inflammatory cells. Later, interstitial fibrosis and atrophy of the papillae and medulla occur and precede these processes in the cortex.

Urinary tract obstruction must always be considered in patients with urinary tract infections or urolithiasis. Urinary stasis encourages the growth of organisms. Urea-splitting bacteria are associated with magnesium ammonium phosphate (struvite) calculi. Hypertension is frequent in acute and subacute unilateral obstruction and is usually a consequence of increased release of renin by the involved kidney. Chronic hydronephrosis, in the presence of extracellular volume expansion, may result in significant hypertension. Erythrocytosis, an infrequent complication of obstructive uropathy, is probably secondary to increased erythropoietin production.

DIAGNOSIS

A history of difficulty in voiding, pain, infection, or changes in urinary volume is common. Evidence for distention of the kidney or urinary bladder can often be obtained by palpation and percussion of the abdomen. A careful rectal examination may reveal enlargement or nodularity of the prostate, abnormal rectal sphincter tone, or a rectal or pelvic mass. The penis should be inspected for evidence of meatal stenosis or phimosis. In the female, vaginal, uterine, and rectal lesions responsible for urinary tract obstruction are usually revealed by inspection and palpation.

Urinalysis may reveal hematuria, pyuria, and bacteriuria. The urine sediment is often normal, even when obstruction leads to marked azotemia and extensive structural damage. An abdominal scout film may detect nephrocalcinosis or a radiopaque stone. As indicated in Fig. 270-1, if urinary tract obstruction is suspected, a bladder catheter should be inserted. If diuresis does not follow, then abdominal ultrasonography should be performed to evaluate renal and bladder size, as well as pyelocalyceal contour. Ultrasonography is approximately 90% specific and sensitive for detection of hydronephrosis. False-positive results are associated with diuresis, renal cysts, or presence of an extrarenal pelvis, a normal congenital variant. Hydronephrosis may be absent on ultrasound when obstruction is associated with volume contraction, staghorn calculi, retroperitoneal fibrosis, or infiltrative renal disease.

In some cases, the intravenous urogram may define the site of obstruction. In the presence of obstruction, the appearance time of the nephrogram is delayed. Eventually the renal image becomes more dense than normal because of slow tubular fluid flow rate, which results in greater concentration of contrast medium. The kidney involved by an acute obstructive process is usually slightly enlarged, and there is dilatation of the calyces, renal pelvis, and ureter above the obstruction. The ureter is not tortuous as in chronic obstruction. In comparison with the nephrogram, the urogram may be faint, especially if the dilated renal pelvis is voluminous, causing dilution of the contrast medium. The radiographic study should be continued until the site of obstruction is determined or the contrast medium is excreted. Radionuclide scans, though sensitive for the detection of obstruction, define less anatomic detail than intravenous urography and, like the urogram, are of limited value when renal function is poor. They have a role in patients at high risk for reaction to intravenous contrast. Patients suspected of having intermittent ureteropelvic obstruction should have radiologic evaluation while in pain, since a normal urogram is commonly seen during asymptomatic periods. Hydration often helps to provoke a symptomatic attack.

To facilitate visualization of a suspected lesion in a ureter or renal pelvis, retrograde or antegrade urography should be attempted. These diagnostic studies may be preferable to the intravenous urogram in the azotemic patient, in whom poor excretory function precludes adequate visualization of the collecting system. Furthermore, intravenous urography carries the risk of contrast-induced acute renal failure in patients with proteinuria, renal insufficiency, diabetes mellitus, or multiple myeloma, particularly if they are dehydrated. The retrograde approach involves catheterization of the involved ureter under cystoscopic control, while the antegrade technique necessitates placement of a catheter into the renal pelvis via a needle inserted percutaneously under ultrasonic or fluoroscopic guidance. While the antegrade approach may provide immediate decompression of a unilateral obstructing lesion, many urologists initially attempt the retrograde approach unless the catheterization is unsuccessful or general anesthesia is contraindicated.

Voiding cystourethrography is of value in the diagnosis of vesicoureteral reflux and bladder neck and urethral obstructions. Patients with obstruction at or below the level of the bladder exhibit thickening, trabeculation, and diverticula of the bladder wall. Postvoiding films reveal residual urine. If these radiographic studies fail to provide adequate information for diagnosis, endoscopic visualization by the urologist often permits precise identification of lesions involving the urethra, prostate, bladder, and ureteral orifices.

Computed tomography (CT) is useful in the diagnosis of specific intraabdominal and retroperitoneal causes of obstruction. The spiral CT is the preferred study to image urinary calculi. Magnetic resonance imaging may also be useful in the identification of specific obstructive causes.

TREATMENT

Urinary tract obstruction complicated by infection requires relief of obstruction as soon as possible to prevent development of generalized sepsis and progressive renal damage. On a temporary basis, drainage is often satisfactorily achieved by nephrostomy, ureterostomy, or ureteral, urethral, or suprapubic catheterization. The patient with acute urinary tract infection and obstruction should be given appropriate antibiotics based on in vitro bacterial sensitivity and the ability of the drug to concentrate in the urine. Treatment may be required for 3 to 4 weeks. Chronic or recurrent infections in an obstructed kidney with poor intrinsic function may necessitate nephrectomy. When infection is not present, immediate surgery often is not required, even in the presence of complete obstruction and anuria because of the availability of dialysis, until acid-base, fluid and electrolyte, and cardiovascular status are restored. Nevertheless, the site of obstruction should be ascertained as soon as feasible, in part because of the possibility that sepsis may occur and this complication necessitates prompt urologic intervention. Elective relief of obstruction is usually recommended in patients with urinary retention, recurrent urinary tract infections, persistent pain, or progressive loss of renal function. Infrequently, mechanical obstruction can be alleviated by nonsurgical means, as with radiation therapy for retroperitoneal lymphoma. Likewise, functional obstruction secondary to neurogenic bladder may be decreased with the combination of frequent voiding and cholinergic drugs. The approach to obstruction secondary to renal stones is discussed in Chap. 268.

PROGNOSIS

With relief of obstruction, the prognosis regarding return of renal function depends largely on whether irreversible renal damage has occurred. When obstruction is not relieved, the course will depend mainly on whether the obstruction is complete or incomplete, bilateral or unilateral, and whether urinary tract infection is also present. Complete obstruction with infection can lead to total destruction of the kidney within days. Partial return of glomerular filtration rate may follow relief of complete obstruction of 1 and 2 weeks' duration but after 8 weeks of obstruction, recovery is unlikely. In the absence of definitive evidence of irreversibility, every effort should be made to decompress the obstruction in the hope of restoring renal function at least partially. A renal radionuclide scan, performed after a prolonged period of decompression, may be used to predict reversible renal function.

POSTOBSTRUCTIVE DIURESIS

Relief of bilateral, but not unilateral, complete obstruction commonly results in polyuria, which may be massive. The urine is usually hypotonic and may contain large amounts of sodium chloride, potassium, and magnesium. The natriuresis is due in part to the excretion of retained urea (osmotic diuresis). The increase in intratubular pressure very likely also contributes to the impairment in net sodium chloride reabsorption, especially in the terminal nephron segments. Natriuretic factors may also accumulate during uremia and depress salt and water reabsorption when urine flow is reestablished. In the majority of patients this diuresis results in the appropriate excretion of the excesses of retained salt and water. When extracellular volume and composition return to normal, the diuresis usually abates spontaneously. Therefore, replacement of urinary losses should only be done in the setting of hypovolemia, hypotension, or disturbances in serum electrolyte concentrations. Occasionally, iatrogenic expansion of extracellular volume is responsible for, or sustains, the diuresis observed in the postobstructive period. Replacement of no more than two-thirds of urinary volume losses per day is usually effective in avoiding this complication. The loss of electrolyte-free water with urea may result in hypernatremia. Serum and urine sodium and osmolal concentrations should guide the use of appropriate intravenous replacement. Often replacement with 0.45% saline is required. In a rare patient, relief of obstruction may be followed by urinary salt and water losses severe enough to provoke profound dehydration and vascular collapse. In these patients, an intrinsic defect in tubule reabsorptive function is probably responsible for the marked diuresis. Appropriate therapy in such patients includes intravenous administration of salt-containing solutions to replace sodium and volume deficits.


	10. tubulointerstitial diseases

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TUBULOINTERSTITIAL DISEASES OF THE KIDNEY - Alan S. L. Yu, Barry M. Brenner

INTRODUCTION

Primary tubulointerstitial diseases of the kidney, as distinct from the disorders considered in Chaps. 264 and 267, are characterized by histologic and functional abnormalities that involve the tubules and interstitium to a greater degree than the glomeruli and renal vasculature (Table 266-1). Secondary tubulointerstitial disease occurs as a consequence of progressive glomerular or vascular injury. Morphologically, acute forms of these disorders are characterized by interstitial edema, often associated with cortical and medullary infiltration by both mononuclear cells and polymorphonuclear leukocytes, and patchy areas of tubule cell necrosis. In more chronic forms, interstitial fibrosis predominates, inflammatory cells are typically mononuclear, and abnormalities of the tubules tend to be more widespread, as evidenced by atrophy, luminal dilatation, and thickening of tubule basement membranes. Because of the nonspecific nature of the histology, particularly in chronic tubulointerstitial diseases, biopsy specimens rarely provide a specific diagnosis. The urine sediment is also unlikely to be diagnostic, except in allergic forms of acute tubulointerstitial disease, in which eosinophils may predominate in the urinary sediment.

Defects in renal function often accompany these alterations of tubule and interstitial structure (Table 266-2). Proximal tubule dysfunction may be manifested as selective reabsorptive defects leading to hypokalemia, aminoaciduria, glycosuria, phosphaturia, uricosuria, or bicarbonaturia [proximal or type II renal tubular acidosis (RTA); Chap. 265]. In combination, these defects constitute the Fanconi syndrome. Proteinuria, predominantly of low-molecular-weight proteins, is usually modest, rarely exceeding 2 g/d.

Defects in urinary acidification and concentrating ability often represent the most troublesome of the tubule dysfunctions encountered in patients with tubulointerstitial disease. Hyperchloremic metabolic acidosis often develops at a relatively early stage in the course. Patients with this finding generally elaborate urine of maximal acidity (pH = 5.3). In such patients the defect in acid excretion is usually caused by a reduced capacity to generate and excrete ammonia due to the reduction in renal mass. Preferential damage to the collecting ducts, as in amyloidosis or chronic obstructive uropathy, may also predispose to distal or type I RTA1, characterized by high urine pH (=5.5) during spontaneous or NH4Cl-induced metabolic acidosis. Patients with tubulointerstitial diseases affecting predominantly medullary and papillary structures may also exhibit concentrating defects, with resultant nocturia and polyuria. Analgesic nephropathy and sickle cell disease are prototypes of this form of injury.

TOXINS

Although the kidney is vulnerable to toxic injury, renal damage by a variety of nephrotoxins often goes unrecognized because the manifestations of such injury are usually nonspecific in nature and insidious in onset. Diagnosis largely depends on a history of exposure to a certain toxin. Particular attention should be paid to the occupational history, as well as to an assessment of exposure — current and remote — to drugs, especially antibiotics and analgesics, and to dietary supplements or herbal remedies. The recognition of a potential association between a patient's renal disease and exposure to a nephrotoxin is crucial, because, unlike many other forms of renal disease, progression of the functional and morphologic abnormalities associated with toxin-induced nephropathies may be prevented, and even reversed, by eliminating additional exposure.

EXOGENOUS TOXINS

Analgesic Nephropathy A distinct clinicopathologic syndrome has been described in heavy users of analgesic mixtures containing phenacetin in combination with aspirin, acetaminophen, or caffeine. Morphologically, analgesic nephropathy is characterized by papillary necrosis and tubulointerstitial inflammation. At an early stage, damage to the vascular supply of the inner medulla (vasa recta) leads to a local interstitial inflammatory reaction and, eventually, to papillary ischemia, necrosis, fibrosis, and calcification. The susceptibility of the renal papillae to damage by phenacetin is believed to be related to the establishment of a renal gradient for its acetaminophen metabolite, resulting in papillary tip concentrations tenfold higher than those in renal cortex. Aspirin in these analgesic compounds contributes to renal injury by uncoupling oxidative phosphorylation in renal mitochondria and by inhibiting the synthesis of renal prostaglandins, which are potent endogenous renal vasodilator hormones.

In analgesic nephropathy, renal function usually declines gradually. Occasionally, papillary necrosis may be associated with hematuria and even renal colic owing to obstruction of a ureter by necrotic tissue. More than half of patients with analgesic nephropathy have pyuria, which, if persistently associated with sterile urine, provides an important clue to the diagnosis. Nonetheless, active pyelonephritis may coexist in patients with analgesic nephropathy. Proteinuria, if present, is typically mild ( 1 g/d). Patients with analgesic nephropathy are usually unable to generate maximally concentrated urine, reflecting the underlying medullary and papillary damage. An acquired form of distal RTA1 (Chap. 265) may contribute to the development of nephrocalcinosis. The occurrence of anemia out of proportion to the degree of azotemia may also provide a clue to the diagnosis of analgesic nephropathy. When analgesic nephropathy has progressed to renal insufficiency, the kidneys usually appear bilaterally shrunken on intravenous pyelography, and the calyces are deformed. A "ring sign" on the pyelogram is pathognomonic of papillary necrosis and represents the radiolucent sloughed papilla surrounded by the radiodense contrast material in the calyx. Computed tomography may reveal papillary calcifications surrounding the central sinus complex in a "garland" pattern. Transitional cell carcinoma may develop in the urinary pelvis or ureters as a late complication of analgesic abuse.

Whether non-phenacetin analgesics, alone or in combination, cause renal disease is controversial. A recent cohort study of men with normal baseline renal function found no association between moderate analgesic use and subsequent renal dysfunction, suggesting that the risk, if any, is low. Until conclusive evidence is available, however, physicians should consider screening heavy users of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) for evidence of renal disease, and discouraging their use of these drugs.

Lead Nephropathy (See also Chap. 376) Lead intoxication may produce a chronic tubulointerstitial renal disease. Children who repeatedly ingest lead-based paints (pica) may develop kidney disease as adults. Significant occupational exposure may occur in workplaces where lead-containing metals or paints are heated to high temperatures, such as battery factories, smelters, salvage yards, and weapon firing ranges. Alcohol, illegally distilled in an apparatus constructed from automobile radiators (so-called moonshine), is another cause of lead poisoning. Environmental lead exposure, particularly in industrial regions, may be great enough to produce changes in renal function.

Tubule transport processes enhance the accumulation of lead within renal cells, particularly in the proximal convoluted tubule, leading to cell degeneration, mitochondrial swelling, and eosinophilic intranuclear inclusion bodies rich in lead. In addition, lead nephropathy is associated with ischemic changes in the glomeruli, fibrosis of the adventitia of small renal arterioles, and focal areas of cortical scarring. Eventually, the kidneys become atrophic. Urinary excretion of lead, porphyrin precursors such as d-aminolevulinic acid and coproporphyrin, and urobilinogen may be increased. Patients with chronic lead nephropathy are characteristically hyperuricemic, a consequence of enhanced reabsorption of filtered urate. Acute gouty arthritis (so-called saturnine gout) develops in about 50% of patients with lead nephropathy, in striking contrast to other forms of chronic renal failure in which de novo gout is rare (Chap. 338). Hypertension is also a complication. Therefore, in any patient with slowly progressive renal failure, atrophic kidneys, gout, and hypertension, the diagnosis of lead intoxication should be considered. Features of acute lead intoxication (abdominal colic, anemia, peripheral neuropathy, and encephalopathy) are usually absent.

The diagnosis may be suspected by finding elevated serum levels of lead. However, because blood levels may not be elevated even in the presence of a toxic total-body burden of lead, the quantitation of lead excretion following infusion of the chelating agent calcium disodium edetate is a more reliable indicator of serious lead exposure. While urinary excretion of more than 0.6 mg/d of lead is generally considered to be indicative of overt or potential toxicity, recent evidence suggests that even lead burdens of 0.15 to 0.6 mg/d may cause progressive loss of renal function.

TREATMENT

Treatment includes removing the patient from the source of exposure and augmenting lead excretion with a chelating agent such as calcium disodium edetate.

Lithium Use of lithium salts for bipolar disorder (Chap. 371) is associated with chronic tubulointerstitial nephropathy, generally manifest as the insidious development of chonic renal insufficiency. Nephrogenic diabetes insipidus, which may occur alone or in association with the renal insufficiency, is common. It manifests as polyuria and polydipsia, and is due to lithium-induced downregulation of the vasopressin-regulated water channels in the collecting duct. Mild proteinuria can occur. The predominant finding on renal biopsy is tubular atrophy and interstitial fibrosis out of proportion to the extent of glomerular or vascular disease. Tubular cysts are common, and concomitant focal segmental glomerulosclerosis can be observed.

Renal function should be followed in patients taking this drug, and caution should be exercised if lithium is employed in patients with underlying renal disease. Once renal impairment occurs, lithium therapy should be stopped and an alternative agent substituted. Despite discontinuation of lithium, chronic renal disease in such patients is often irreversible and can progress to end-stage renal failure.

Miscellaneous Nephrotoxins The immunosuppressant cyclosporine causes both acute and chronic renal injury. The acute injury and the use of cyclosporine in transplantation are discussed in Chap. 263. The chronic injury results in an irreversible reduction in glomerular filtration rate (GFR), with mild proteinuria and arterial hypertension. Hyperkalemia is a relatively common complication and results in part from tubule resistance to aldosterone. The histologic changes in renal tissue include patchy interstitial fibrosis and tubular atrophy. In addition, the intrarenal vasculature often demonstrates hyalinosis, and focal segmental glomerular sclerosis can be present as well. Fibrosis may be the result of a cyclosporine-induced increase in renal collagen production. Vasoconstrictive mediators, such as angiotensin II, may also play a role in chronic cyclosporine toxicity. In patients receiving this drug for renal transplantation (Chap. 263), chronic graft dysfunction and recurrence of the primary disease may coincide with chronic cyclosporine injury, and on clinical grounds, distinction among these may be difficult. Cyclosporine nephrotoxicity is also seen in patients undergoing heart or lung transplantation, as well as in patients receiving cyclosporine as an immunosuppressant in a variety of inflammatory and autoimmune disorders. Dose reduction appears to mitigate cyclosporine-associated renal fibrosis but may increase the risk of rejection and graft loss. Treatment of any associated arterial hypertension may lessen renal injury.

Chinese herbs nephropathy is characterized by rapidly progressive interstitial renal fibrosis in young women due to ingestion of slimming pills containing Chinese herbs. At least one of the culprit ingredients is aristolochic acid. Clinically, patients present with progressive chronic renal insufficiency with sterile pyuria and anemia that is disproportionately severe relative to the level of renal function. The pathologic findings are interstitial fibrosis and tubular atrophy that affects the cortex in preference to the medulla, fibrous intimal thickening of the interlobular arteries, and a relative paucity of cellular infiltrates.

Many agents that commonly lead to acute renal failure are also capable of producing tubulointerstitial injury (Chap. 260). These include antibiotics (e.g., aminoglycosides, amphotericin B), radiographic contrast agents, various hydrocarbons (e.g., carbon tetrachloride), and heavy metals (e.g., mercury, cadmium, and bismuth).

METABOLIC TOXINS

Acute Uric Acid Nephropathy (See also Chap. 313) Acute overproduction of uric acid and extreme hyperuricemia often lead to a rapidly progressive renal insufficiency, so-called acute uric acid nephropathy. This tubulointerstitial disease is usually seen as part of the tumor lysis syndrome in patients given cytotoxic drugs for the treatment of lymphoproliferative or myeloproliferative disorders but may also occur in these patients before such treatment is begun. The pathologic changes are largely the result of deposition of uric acid crystals in the kidneys and their collecting systems, leading to partial or complete obstruction of collecting ducts, renal pelvis, or ureter. Since obstruction is often bilateral, patients typically follow the clinical course of acute renal failure, characterized by oliguria and rapidly rising serum creatinine concentration. In the early phase uric acid crystals can be found in urine, usually in association with microscopic or gross hematuria. Hyperuricemia can also be a consequence of renal failure of any etiology. The finding of a urine/uric acid creatinine ratio greater than 1 mg/mg (0.7 mol/mol) distinguishes acute uric acid nephropathy from other causes of renal failure.

Prevention of hyperuricemia in patients at risk by treatment with allopurinol in doses of 200 to 800 mg/d prior to cytotoxic therapy reduces the danger of acute uric acid nephropathy. Once hyperuricemia develops, however, efforts should be directed to preventing deposition of uric acid within the urinary tract. Increasing urine volume with potent diuretics (furosemide or mannitol) effectively lowers intratubular uric acid concentrations, and alkalinization of the urine to pH 7 or greater with sodium bicarbonate and/or a carbonic anhydrase inhibitor (acetazolamide) enhances uric acid solubility. If these efforts, together with allopurinol therapy, are ineffective in preventing acute renal failure, dialysis should be instituted to lower the serum uric acid concentration as well as to treat the acute manifestations of uremia.

Gouty Nephropathy (See also Chap. 313) Patients with less severe but prolonged forms of hyperuricemia are predisposed to a more chronic tubulointerstitial disorder, often referred to as gouty nephropathy. The severity of renal involvement correlates with the duration and magnitude of the elevation of the serum uric acid concentration. Histologically, the distinctive feature of gouty nephropathy is the presence of crystalline deposits of uric acid and monosodium urate salts in kidney parenchyma. These deposits not only cause intrarenal obstruction but also incite an inflammatory response, leading to lymphocytic infiltration, foreign-body giant cell reaction, and eventual fibrosis, especially of medullary and papillary regions of the kidney. Bacteriuria and pyelonephritis occur in about one-fourth of cases, presumably as complications of intrarenal urinary stasis. Since patients with gout frequently suffer from hypertension and hyperlipidemia, degenerative changes of the renal arterioles may constitute a striking feature of the histologic abnormality, often out of proportion to other morphologic defects. Clinically, gouty nephropathy is an insidious cause of renal insufficiency. Early in its course, GFR2 may be near normal, often despite focal morphologic changes in medullary and cortical interstitium, proteinuria, and diminished urinary concentrating ability. Whether reducing serum uric acid levels with allopurinol exerts a beneficial effect on the kidney remains to be demonstrated. Although such undesirable consequences of hyperuricemia as gout and uric acid stones respond well to allopurinol, use of this drug in asymptomatic hyperuricemia has not been shown to improve renal function consistently. On the other hand, uricosuric agents such as probenecid, which may increase uric acid stone production, clearly have no role in the treatment of renal disease associated with hyperuricemia.

Hypercalcemic Nephropathy (See also Chap. 332) Chronic hypercalcemia, as occurs in primary hyperparathyroidism, sarcoidosis, multiple myeloma, vitamin D intoxication, or metastatic bone disease, can cause tubulointerstitial damage and progressive renal insufficiency. The earliest lesion is a focal degenerative change in renal epithelia, primarily in collecting ducts, distal convoluted tubules, and loops of Henle. Tubule cell necrosis leads to nephron obstruction and stasis of intrarenal urine, favoring local precipitation of calcium salts and infection. Dilatation and atrophy of tubules eventually occur, as do interstitial fibrosis, mononuclear leukocyte infiltration, and interstitial calcium deposition (nephrocalcinosis). Calcium deposition may also occur in glomeruli and the walls of renal arterioles.

Clinically, the most striking defect is an inability to concentrate the urine maximally, resulting in polyuria and nocturia. Reduced collecting duct responsiveness to vasopressin and defective transport of NaCl in the ascending limb of Henle's loop are responsible for this concentrating defect. Reductions in GFR3 and renal blood flow also occur, both in acute severe hypercalcemia and with prolonged hypercalcemia of lesser severity. Distal RTA1 and sodium and potassium wasting have also been described in these chronic states. Eventually, uncontrolled hypercalcemia leads to severe tubulointerstitial damage and overt renal failure. Abdominal x-rays may demonstrate nephrocalcinosis as well as nephrolithiasis, the latter due to the hypercalciuria that often accompanies hypercalcemia.

TREATMENT

This consists of reducing the serum calcium concentration toward normal and correcting the primary abnormality of calcium metabolism. The management of hypercalcemia is discussed in Chap. 332. Prognosis for recovery of renal function depends on the severity of the renal lesion at the time hypercalcemia is corrected. Renal dysfunction of acute hypercalcemia may be completely reversible. Gradual, progressive renal insufficiency related to chronic hypercalcemia, however, may not improve with correction of the calcium disorder. Nonetheless, every effort should be made to return serum calcium concentration to normal to minimize further loss of renal function.

RENAL PARENCHYMAL DISEASE ASSOCIATED WITH EXTRARENAL NEOPLASM

Except for the glomerulopathies associated with lymphomas and several solid tumors (Chap. 264), the renal manifestations of primary extrarenal neoplastic processes are confined mainly to the interstitium and tubules. Although metastatic renal involvement by solid tumors is unusual, the kidneys are often invaded by neoplastic cells in hematologic malignancies. In postmortem studies of patients with lymphoma and leukemia, renal involvement is found in approximately half. Diffuse infiltration of the renal parenchyma with malignant cells is seen most commonly. There may be flank pain, and x-rays may show enlargement of one or both kidneys. Renal insufficiency occurs in a minority of cases, and overt uremia is rare. Treatment of the primary disease may improve renal function in these cases.

PLASMA CELL DYSCRASIAS

Several glomerular and tubulointerstitial disorders may occur in association with plasma cell dyscrasias (Chap. 98). Infiltration of the kidneys with myeloma cells is infrequent. When it occurs, the process is usually focal, so renal insufficiency from this cause is also uncommon. The more usual lesion is myeloma kidney, characterized histologically by atrophic tubules, many with eosinophilic intraluminal casts, and numerous multinucleated giant cells within tubule walls and in the interstitium. The frequent occurrence of myeloma kidney in patients with Bence Jones proteinuria has suggested a causal relation. Bence Jones proteins are thought to cause myeloma kidney through direct toxicity to renal tubule cells. In addition, Bence Jones proteins may precipitate within the distal nephron where the high concentrations of these proteins and the acid composition of the tubule fluid favor intraluminal cast formation and intrarenal obstruction. Occasionally, acute renal failure occurs after intravenous pyelography in patients with multiple myeloma and is believed to result from the further precipitation of Bence Jones proteins induced by dehydration prior to radiographic study. Dehydration of the patient with myeloma in preparation for intravenous pyelography should therefore be avoided. Multiple myeloma may also affect the kidneys indirectly. Hypercalcemia or hyperuricemia may lead to the nephropathies described above. Proximal tubule disorders are also seen occasionally, including type II proximal RTA1 and the Fanconi syndrome.

AMYLOIDOSIS (SEE ALSO CHAPS. 264 AND 310)

Glomerular pathology usually predominates and leads to heavy proteinuria and azotemia. However, tubule function may also be deranged, giving rise to a nephrogenic diabetes insipidus and to distal (type I) RTA1. In several cases these functional abnormalities correlated with peritubular deposition of amyloid, particularly in areas surrounding vasa rectae, loops of Henle, and collecting ducts. Bilateral enlargement of the kidneys, especially in a patient with massive proteinuria and tubule dysfunction, should raise the possibility of amyloid renal disease.

IMMUNE DISORDERS

ALLERGIC INTERSTITIAL NEPHRITIS

An acute diffuse tubulointerstitial reaction may result from hypersensitivity to a number of drugs, including sulfonamides, many penicillins and cephalosporins, the fluoroquinolone antibiotics ciprofloxacin and norfloxacin, and the antituberculous drugs isoniazid and rifampin. Acute tubulointerstitial damage has also occurred after use of thiazide and loop diuretics, antiulcer medications (cimetidine, ranitidine, and omeprazole), allopurinol, and NSAIDs4. Of note, the tubulointerstitial nephropathy that develops in some patients taking NSAIDs may be associated with nephrotic-range proteinuria and histologic evidence of either minimal change or membranous glomerulopathy. The use of mesalazine for the treatment of inflammatory bowel disease is associated with a more subacute disorder in which a severe indolent interstitial nephritis occurs several months after the initiation of the drug. Grossly, the kidneys are usually enlarged. Histologically, the glomeruli appear normal. The principal pathologic abnormalities are in the interstitium of the kidney, which reveals pronounced edema and infiltration with polymorphonuclear leukocytes, lymphocytes, plasma cells, and, in some cases, large numbers of eosinophils. If the process is severe, tubule cell necrosis and regeneration may also be apparent. Immunofluorescence studies have either been unrevealing or demonstrated a linear pattern of immunoglobulin and complement deposition along tubule basement membranes.

Most patients require several weeks of drug exposure before developing evidence of renal injury. Rare cases have occurred after only a few doses or after a year or more of use. Azotemia is usually present; a diagnostic triad of fever, skin rash, and peripheral blood eosinophilia is highly suggestive of acute tubulointerstitial nephritis but is often absent. Examination of the urine sediment reveals hematuria and often pyuria; occasionally, eosinophils may be present. Proteinuria is usually mild to moderate, except in cases of NSAID5-induced tubulointerstitial nephritis with minimal change glomerulopathy. The clinical picture may be confused with acute glomerulonephritis, but when acute azotemia and hematuria are accompanied by eosinophilia, skin rash, and a history of drug exposure, a hypersensitivity reaction leading to acute tubulointerstitial nephritis should be regarded as the leading diagnostic possibility. Discontinuation of the drug usually results in complete reversal of the renal injury; rarely, renal damage may be irreversible. Glucocorticoids may accelerate renal recovery, but their value has not been definitively established.

SJOGREN'S SYNDROME (SEE ALSO CHAP. 304)

When the kidneys are involved in this disorder, the predominant histologic findings are those of chronic tubulointerstitial disease. Interstitial infiltrates are composed primarily of lymphocytes, causing the histology of the renal parenchyma in these patients to resemble that of the salivary and lacrimal glands. Renal functional defects include diminished urinary concentrating ability and distal (type I) RTA1. Urinalysis may show pyuria (predominantly lymphocyturia) and mild proteinuria.

TUBULOINTERSTITIAL ABNORMALITIES ASSOCIATED WITH GLOMERULONEPHRITIS

Primary glomerulopathies are often associated with damage to tubules and the interstitium. Occasionally, the primary disorder may affect glomeruli and tubules directly. For example, in more than half of patients with the nephropathy of systemic lupus erythematosus, deposits of immune complexes can be identified in tubule basement membranes, usually accompanied by an interstitial mononuclear inflammatory reaction. Similarly, in many patients with glomerulonephritis associated with anti-glomerular basement membrane antibody, the same antibody is reactive against tubule basement membranes as well. More frequently, tubulointerstitial damage is a secondary consequence of glomerular dysfunction. The extent of tubulointerstitial fibrosis correlates closely with the degree of renal impairment. Potential mechanisms by which glomerular disease might cause tubulointerstitial injury include glomerular leak of plasma proteins toxic to epithelial cells, activation of tubule epithelial cells by glomerulus-derived cytokines, reduced peritubular blood flow leading to downstream tubulointerstitial ischemia, and hyperfunction of remnant tubules.

MISCELLANEOUS DISORDERS

VESICOURETERAL REFLUX (SEE ALSO CHAP. 270)

When the function of the ureterovesical junction is impaired, urine may reflux into the ureters due to the high intravesical pressure that develops during voiding. Clinically, reflux is often detected on the voiding and postvoiding films obtained during intravenous pyelography, although voiding cystourethrography may be required for definitive diagnosis. Bladder infection may ascend the urinary tract to the kidneys through incompetent ureterovesical sphincters. Not surprisingly, therefore, reflux is often discovered in patients with acute and/or chronic urinary tract infections. With more severe degrees of reflux, characterized by dilatation of ureters and renal pelves, progressive renal damage often appears, and although active infection may also be present, uncertainty exists as to the necessity of infection in producing the scarred kidney of reflux nephropathy. Substantial proteinuria is often present, and glomerular lesions similar to those of idiopathic focal glomerulosclerosis (Chap. 264) are often found in addition to the changes of chronic tubulointerstitial disease. Surgical correction of reflux is usually necessary only with the more severe degrees of reflux since renal damage correlates with the extent of reflux. Obviously, if extensive glomerulosclerosis already exists, urologic repair may no longer be warranted.

RADIATION NEPHRITIS

Renal dysfunction can be expected to occur if 23 Gy (2300 rad) or more of x-ray irradiation is administered to both kidneys during a period of 5 weeks or less. Histologic examination of the kidneys reveals hyalinized glomeruli, atrophic tubules, extensive interstitial fibrosis, and hyalinization of the media of renal arterioles. Radiation-induced renal ischemia is believed to be the main pathogenic factor responsible for the tubulointerstitial damage, which may not become evident clinically for months after completion of radiation. The presentation of acute radiation nephritis includes rapidly progressive azotemia, moderate to malignant hypertension, anemia, and proteinuria that may reach the nephrotic range. More than 50% progress to chronic renal failure. A more insidious form is characterized by slower development of azotemia, anemia, and nephrotic syndrome. Malignant hypertension may follow unilateral renal irradiation and resolve with ipsilateral nephrectomy. Radiation nephritis has all but vanished because of heightened awareness of its pathogenesis by radiotherapists.


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